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Disentangling the role of the tau gene locus in sporadic tauopathies
Vandrovcova J, Anaya F, Kay V, Lees A, Hardy J, de Silva R.
[Abstract] [Purchase Article] [PMID: 20704554 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00001]


Chromosome 17 in FTLD: from MAPT Tau to Progranulin and back
Alberici A, Cosseddu M, Padovani A, Borroni B
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21222603 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/000002]


Mitochondria: the common upstream driver of Abeta and Tau pathology in Alzheimer´s disease
Diana FF. Silva, Esteves AR, Oliveira CR, Cardoso SM
[Abstract] [Purchase Article] [PMID: 21244356 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00003]


Biochemical Differentiation of Cholinesterases from  Normal and Alzheimer's Disease Cortex
Ciro A, Park J, Burkhard G, Yan N, Geula C
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21244353 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00004]


Aβ Oligomers Induce Glutamate Release from Hippocampal Neurons
Brito-Moreira J, Paula-Lima AC, Bomfim TR, Oliveira FB, Sepúlveda FJ, De Mello FG, Aguayo LG, Panizzutti R, Ferreira ST
[Abstract] [Purchase Article] [PMID: 21244351 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00005]


Determination of spatial and temporal distribution of microglia by 230nm-high-resolution, high-throughput automated analysis reveals different amyloid plaque populations in an APP/PS1 mouse model of Alzheimer’s disease
Scheffler K, Stenzel J, Krohn M, Lange C, Hofrichter J, Schumacher T, Brüning T, Plath A-S, Walker L, Pahnke J
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21244350 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00006]


The potential dual effects of anesthetic isoflurane on Aβ-induced apoptosis
Xu Z,  Dong Y, Wu X, Zhang J, McAuliffe S, Pan C, Zhang Y, Ichinose F, Yue Y, Xie Z
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21519046 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00007]


Editorial:
[BSP/CAR/E-Pub/00009]


The AICD interacting protein DAB1 is up-regulated in Alzheimer frontal cortex brain samples and causes deregulation of proteins involved in gene expression changes
Müller T, Loosse C, Schrötter A, Schnabel A, Helling S, Egensperger R, Marcus K
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21453247 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00010]


Chronic Psychosocial Stress Exacerbates Impairment of Synaptic Plasticity in β-Amyloid Rat Model of Alzheimer’s Disease: Prevention by Nicotine
Alkadhi KA, Alzoubi KH, Srivareerat M and Tran  TT
[Abstract] [Purchase Article] [PMID: 21453245 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00011]


Voluntary running and environmental enrichment restores impaired hippocampal neurogenesis in a triple transgenic mouse model of Alzheimer’s disease
Rodríguez JJ, Noristani HN, Olabarria M, Fletcher J, Somerville TDD, Yeh  CY, Verkhratsky A
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21453244 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00012]


Recent breakthroughs in the understanding of Frontotemporal Lobar Degeneration and its related disorders.
Borroni B
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21524272 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00013]


The Overlapping Syndromes of the Pick Complex
Kertesz A
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21524271 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00014]


Effect of Cholinergic Stimulation in Early Alzheimer’s Disease – Functional Imaging During a Recognition Memory Task
Miettinen PS, Pihlajamäki M, Jauhiainen AM, Tarkka IM, Gröhn H, Niskanen E, Hänninen T, Vanninen R, Soininen H
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21592058 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00015]


Mobilization and redistribution of default mode network from resting state to task state in amnestic mild cognitive impairment
Bai F, Watson DR, Shi Y, Yuan Y, Yu H, Zhang Z
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21592057 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00016]


Follow-up Study of Olfactory Deficits, Cognitive Function, and Volume Loss of Medial Temporal Lobe Structures in Patients with Mild Cognitive Impairment
Lojkowska W, Sawicka B, Gugala M, Sienkiewicz-Jarosz H, Bochynska A, Scinska A, Korkosz A, Lojek E, Ryglewicz D
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21592056 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00017]


Anti-β-amyloid Immunotherapy for Alzheimer’s Disease: Focus on Bapineuzumab
Panza F, Frisardi V, Imbimbo BP, Seripa D, Paris F, Santamato A, D’Onofrio G, Logroscino G, Pilotto A, Solfrizzi V
[Abstract] [Purchase Article] [PMID: 21592055 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00018]


Dysregulated NF-κB pathway in peripheral mononuclear cells of Alzheimer’s disease patients
Ascolani A, Balestrieri E, Minutolo A, Mosti S, Spalletta G, Bramanti P, Mastino A, Caltagirone C, Macchi B
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21592054 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00019]


Amyloid ß Peptide Levels Increase in Brain of AßPP Swedish Mice after Exposure to Chlorpyrifos
Salazar JG, Ribes D, Cabré M, Domingo JL, Sanchez-Santed F, Colomina MT
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21592053 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00020]


Transgenic Mice as a Model for Alzheimer’s Disease
Lithner CU, Hedberg MM, Nordberg A
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21592052 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00021]


Aβ(1-42) Aggregates into non-Toxic Amyloid Assemblies in the Presence of the Natural Polyphenol Oleuropein Aglycon
Rigacci S, Guidotti V, Bucciantini M, Nichino D, Relini A, Berti A, Stefani M
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21592051 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00022]


Left Anterior Temporal Lobe Sustains Naming in Alzheimer's Dementia and Mild Cognitive Impairment
Frings L, Klöppel S, Teipel S, Peters O, Frölich L, Pantel J, Schröder J, Gertz H-J, Arlt S, Heuser I, Kornhuber J, Wiltfang J, Maier W, Jessen F, Hampel H, Hüll M
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21592050 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00023]


Effects of Coenzyme Q and Creatine Supplementation on Brain Energy Metabolism in Rats Exposed to Chronic Cerebral Hypoperfusion
Horecky J, Gvozdjáková A, Kucharská J, Obrenovich ME, Palacios HH, Li Y, Vancová O, Aliev G
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21592049 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00024]


Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: Two phase 3 studies
Harrington C, Sawchak S, Chiang C, Davies J, Donovan C, Saunders AM, Irizarry M, Jeter B, Zvartau-Hind M, van Dyck CH, Gold M
[Abstract] [Purchase Article] [PMID: 21592048 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00025]


Mild Cognitive Impairment (MCI) – the novel trend of targeting Alzheimer`s disease in its early stages - Methodological considerations.
Pater C
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21592047 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00026]


Mechanisms of tau selfaggregation and neurotoxicity
Farías G, Cornejo A, Jiménez J, Guzmán L,  Maccioni RB
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605046 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00027]


Pin1: a new outlook in Alzheimer Disease
Elena L, Massimo M, Alessandra B
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605045 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00028]


Role of protein phosphatase 2A in Alzheimer’s Disease
Rudrabhatla P, Pant HC
[Abstract] [Purchase Article] [PMID: 21605044 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00029]


Loss of medial septum cholinergic neurons in THY-Tau22 mouse model: what links with tau pathology?
Belarbi K, Burnouf S, Fernandez-Gomez F-J, Desmercières J, Troquier L, Brouillette J, Tsambou L, Grosjean M-E, Caillierez R, Demeyer D, Hamdane M, Schindowski K, Blum D, Buée L
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605043 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00030]


A Novel Perspective on Tau in Alzheimer Disease
Bonda DJ, Castellani RJ, Zhu X, Nunomura A, Lee H-G, Perry G, Smith MA
[Abstract] [Purchase Article] [PMID: 21605042 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00031]


Abl tyrosine kinase signaling: A new player in AD Tau pathology.
Estrada LD , Zanlungo  SM, Alvarez AR
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605041 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00032]


Molecular targets in the rational design of AD specific PET tracers:  tau or amyloid aggregates?
Rojo LE, Gaspar P, Maccioni RB
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605040 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00033]


Tau oligomers as potential target for immunotherapy for Alzheimer disease and tauopathies
Lasagna-Reeves CA, Castillo-Carranza DL, Jackson GR, Kayed R
[Abstract] [Purchase Article] [PMID: 21605039 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00034]


Novel drugs affecting tau behavior in the treatment of Alzheimer´s disease and tauopathies
Navarrete LP, Pérez P, Morales I, Maccioni RB
[Abstract] [Purchase Article] [PMID: 21605038 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00035]


A clinical perspective: anti tau’s treatment in  Alzheimer´s Disease
Fuentes P, Catalan J
[Abstract] [Purchase Article] [PMID: 21605037 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00036]


The Role of the Anti-Amyloidogenic Secretase ADAM10 in Shedding the APP-like Proteins
Endres K, Fahrenholz F
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605036 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00037]


AICD nuclear signaling and its possible contribution to Alzheimer’s disease
Konietzko U
[Abstract] [Purchase Article] [PMID: 21605035 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00038]


BACE1 dependent Neuregulin proteolysis
Fleck D, Garratt AN, Haass C, Willem M
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605034 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00039]


Alpha-Secretase Cleavage of the Amyloid Precursor Protein: Proteolysis Regulated by Signaling Pathways and Protein Trafficking
Lichtenthaler SF
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605033 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00040]


An Overview of Notch Signaling in Adult Tissue Renewal and Maintenance
Sato C, Zhao G, Ilagan MXG
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605032 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00041]


BDNF serum concentrations show no relationship with diagnostic group or medication status in neurodegenerative disease
Woolley JD, Strobl EV, Shelly WB, Miller BL, Mellon SH, Rankin KP
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605064 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00042]


Genetic polymorphisms in sigma-1 receptor and apolipoprotein E interact to influence the severity of Alzheimer's disease
Huang Y, Zheng L, Halliday G, Dobson-Stone C, Wang Y, Tang HD, Cao L, Deng YL, Wang G, Zhang YM, Wang JH, Hallupp M, Kwok J, Chen SD
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605063 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00043]


The role for oxidative stress in aberrant DNA methylation in Alzheimer's Disease
Fleming JL, Phiel CJ, Toland AE
[Abstract] [Purchase Article] [PMID: 21605062 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00044]


The Ability of Tolfenamic Acid to Penetrate the Brain: A Model for Testing the Brain Disposition of Candidate Alzheimer's Drugs Using Multiple Platforms
Subaiea GM, Alansi BH, Serra DA, Alwan M, and Zawia NH
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605061 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00045]


α‐Secretase in Alzheimer’s Disease and Beyond: Mechanistic, Regulation and Function in the Shedding of Membrane Proteins
Vincent B, Checler F
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605031 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00046]


γ-Secretase, apolipoprotein E and cellular cholesterol metabolism
Walter J
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605030 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00047]


Role of APP and Aβ in Synaptic Physiology
Wang Z, Yang L, Zheng H
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605029 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00048]


Dietary omega 3 polyunsaturated fatty acids and Alzheimer’s disease: Interaction with apolipoprotein E genotype
Barberger-Gateau  P, Samieri C, Féart C, Plourde  M
[Abstract] [Purchase Article] [PMID: 21605054 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00049]


Possible involvement of programmed cell death pathways in the neuroprotective action of polyphenols
Bastianetto S, Krantic S, Chabot J-G, Quirion R
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605053 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00050]


Nutritional Approaches to Modulate Oxidative Stress in Alzheimer’s Disease
Pocernich CB, Bader Lange ML, Sultana R, Butterfield DA
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605052 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00051]


Omega-3 polyunsaturated fatty acids in Alzheimer’s disease: key questions and partial answers
Calon F
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605051 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00052]


Metabolic Syndrome, Mild Cognitive Impairment, and Dementia
Panza F, Frisardi V, Seripa D, Imbimbo BP, Sancarlo D, D’Onofrio G, Addante F, Paris F, Pilotto A, Solfrizzi V
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605050 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00053]


Tyrosol and hydroxytyrosol, two main components of olive oil, protect N2a cells against amyloid-β-induced toxicity. Involvement of the NF-κB signaling
St-Laurent-Thibault C,  Arseneault M,  Longpré F, Ramassamy C
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605049 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00054]


Dietary patterns in Alzheimer’s disease and cognitive aging
Gu Y, Scarmeas N
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605048 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00055]


Mediterranean Diet in Predementia and Dementia Syndromes
Solfrizzi V, Frisardi V, Seripa D, Logroscino G, Imbimbo BP, D’Onofrio G, Addante F, Sancarlo D,  Cascavilla L, Pilotto A, Panza F
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21605047 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00056]


Association and Causal Relationship of Midlife Obesity and Related Metabolic Disorders with Old Age Cognition
Laitala VS, Kaprio J, Koskenvuo M, Räihä I,  Rinne JO and  Silventoinen K
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21619517 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00057]


Tau as A Therapeutic Target for Alzheimer’s Disease
Boutajangout A, Sigurdsson EM, Krishnamurthy PK
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21679154 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00058]


Effects of Galantamine in Alzheimer’s Disease: Double-blind Withdrawal Studies Evaluating Sustained Versus Interrupted Treatment
Gaudig M, Richarz U, Han J, Baelen BV, Schäuble B
[Abstract] [Purchase Article] [PMID: 21707533 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00059]


Editorial: Tau protein and Alzheimer´s disease
Maccioni RB
[BSP/CAR/E-Pub/00060]


Metric distances between hippocampal shapes indicate different rates of change over time in nondemented and demented subjects
Ceyhan E, Beg MF, Ceritoğlu C, Wang L, Morris JC, Csernansky JG, Miller MI and Ratnanather JT
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21875412 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00061]


Dogs with Cognitive Dysfunction Syndrome: A Natural Model of Alzheimer’s Disease
Bosch MN, Pugliese M, Gimeno-Bayón J, Rodríguez MJ and Mahy N
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21875411 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00062]


Influence of Lithium Treatment on GDNF Serum and CSF Concentrations in Patients with Early Alzheimer´s Disease
Straten G, Saur R, Laske C, Gasser T, Annas P, Basun H and Leyhe T
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21875410 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00063]


Matrix Metalloproteinase-2 and Epidermal Growth Factor are Decreased in Platelets of Alzheimer Patients
Hochstrasser T, Ehrlich D, Marksteiner J, Sperner-Unterweger B and Humpel C
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21875409 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00064]


Optimized turmeric extract reduces β-Amyloid and phosphorylated Tau protein burden in Alzheimer’s transgenic mice
Douglas Shytle R, Tan J, Bickford PC, Rezai-zadeh K, Hou L, Zeng J, Sanberg PR, Sanberg CD, Alberte RS, Fink RC, and Roschek Jr. B
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21875408 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00065]


N-Methyl D-Aspartate (NMDA) Receptor Antagonists and Memantine Treatment for Alzheimer’s Disease, Vascular Dementia and Parkinson’s Disease
Olivares D, Deshpande VK, Shi Y, Lahiri DK, Greig NH, Rogers JT and Huang X
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21875407 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00066]


Stage-dependent agreement between cerebrospinal fluid proteins and FDG-PET findings in Alzheimer’s disease
Yakushev I, Müller MJ, Buchholz H-G, Lang U, Rossmann H, Hampel H, Schreckenberger M and Fellgiebel A
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00067]


Intrahippocampal Amyloid-β (1-40) Injections Injure Medial Septal Neurons in Rats
Colom LV, Castaneda MT, Hernandez S, Perry G, Jaime S and Touhami A
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00068]


Altered calmodulin degradation and signaling in non-neuronal cells from Alzheimer’s disease patients
Esteras N, Muñoz U, Alquézar C, Bartolomé F, Bermejo-Pareja F and Martín-Requero A
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00069]


Association of SORL1 alleles with late-onset Alzheimer's Disease. Findings from the GIGAS_LOAD study and mega-analysis
Olgiati P, Politis A, Albani D, Rodilossi S, Polito L, Ateri E, Zisaki A, Piperi C, Liappas I, Stamouli E, Mailis A, Atti AR, Ferrari B, Morini V, Moretti F, Biella G, Forloni G, Papadimitriou GN, De Ronchi D, Kalofoutis A and Serretti A
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00070]


Tissue Distribution and Pharmacodynamics of Rivastigmine after Intranasal and Intravenous Administration in Rats
Yang Z-Z, Zhang Y-Q, Wu K, Wang Z-Z and Qi X-R
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00071]


Deciphering the Physiology Underlying the Rapid Clinical Effects of Perispinal Etanercept in Alzheimer’s Disease
Edward Tobinick
[Abstract] [Purchase Article] [PMID: 22191562 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00072]


Galantamine-based hybrid molecules with acetylcholinesterase, butyrylcholinesterase and γ-secretase inhibition activities
Vezenkova L, Sevalle J, Danalev D, Ivanov T, Bakalova A, Georgieva M and Checler F
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00073]


Disturbed sleep patterns in elders with mild cognitive impairment: The role of memory decline and ApoE ε4 genotype
Hita-Yañez E, Atienza M, Gil-Neciga E and Cantero JL
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00074]


Effects of Cholinergic Enhancing Drugs on Cholinergic Transporters in the Brain and Peripheral Blood Lymphocytes of Spontaneously Hypertensive Rats
Tomassoni D, Catalani A, Cinque C, Antonietta di Tullio M, Tayebati SK, Cadoni A, Nwankwo IE, Traini E and Amenta F
[Abstract] [Purchase Article] [PMID: 22191561 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00075]


Combining Neuropsychological and Structural Neuroimaging Indicators of Conversion to Alzheimer’s Disease in Amnestic Mild Cognitive Impairment
Venneri A, Gorgoglione G, Toraci C, Nocetti L, Panzetti P and Nichelli P
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00076]


Evolution of global and local grey matter atrophy on serial MRI scans during the progression from MCI to AD
Spulber G, Niskanen E, MacDonald S, Kivipelto M, Padilla DF, Julkunen V, Hallikainen M, Vanninen R, Wahlund L-O and Soininen H
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00077]


Gender-dependent levels of hyaluronic acid in cerebrospinal fluid of patients with neurodegenerative dementia
Henrietta M Nielsen, Sebastian Palmqvist, Lennart Minthon, Elisabet Londos and Malin Wennström
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00078]


Threshold-independent meta-analysis of Alzheimer`s disease transcriptomes shows progressive changes in hippocampal functions, epigenetics and microRNA regulation
Barbash S and Soreq H
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00079]


Cognitive Abilities of Alzheimer’s Disease Transgenic Mice are Modulated by Social Context and Circadian Rhythm
Kiryk A, Mochol G, Filipkowski RK, Wawrzyniak M, Lioudyno V, Knapska E, Gorkiewicz T, Balcerzyk M, Leski S, Leuven FV, Lipp H-P, Wojcik DK and Kaczmarek L
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00080]


Effects of the Putative Cognitive-Enhancing Ampakine, CX717, on Attention and Object Recognition Memory
Zheng Y, Balabhadrapatruni S, Masumura C, Darlington CL and Smith PF
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00081]


Trehalose protects from aggravation of amyloid pathology induced by isoflurane anesthesia in APP_swe mutant mice
Perucho J, Casarejos MJ, Gomez A, Solano RM, Garcia de Yébenes J and Mena MA
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00082]


Granular Non-fibrillar Aggregates and Toxicity in Alzheimer’s Disease
Benseny-Cases N, Klementieva O, Malý J and Cladera J
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00083]


The association of ACT -17 A/T polymorphism with Alzheimer’s disease: a meta-analysis
Dou C, Zhang J, Sun Y, Zhao X, Wu Q, Ji C, Gu S, Xie Y and Mao Y
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00084]


Allopregnanolone Increases the Number of Dopaminergic Neurons in Substantia Nigra of Triple Transgenic Mouse Model of Alzheimer’s Disease
Sun C, Ou X, Farley JM, Stockmeier C, Bigler S, Brinton RD and Wang JM
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00085]


Pilot Randomized Controlled Study of a Histamine Receptor Inverse Agonist in the Symptomatic Treatment of AD
Egan M, Yaari R, Liu L, Ryan M, Peng Y, Lines C and Michelson D
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00086]


Neurosteroid PREGS protects neurite growth and survival of newborn neurons in the hippocampal dentate gyrus of APPswe/PS1dE9 mice
Xu B, Yang R, Chang F, Chen L, Xie G, Sokabe M and Chen L
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00087]


White Matter Damage along the Uncinate Fasciculus Contributes to Cognitive Decline in AD and DLB
Serra L, Cercignani M, Basile B, Spanò B, Perri R, Fadda L, Marra C, Giubilei F, Caltagirone C and Bozzali M
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00088]


Low-dose Radiation Stimulates Wnt/β-catenin Signaling, Neural Stem Cell Proliferation and Neurogenesis of the Mouse Hippocampus in vitro and in vivo
Wei L-C, Ding Y-X, Liu Y-H, Duan L, Bai Y, Shi M and Chen L-W
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00089]


Common variants in toll-like receptor 4 confer susceptibility to Alzheimer’s disease in a Han Chinese population
Yu J-T , Miao D, Cui W-Z, Ou J-R, Tian Y, Wu Z-C, Zhang W and Tan L
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00090]


Pharmacological inhibition of PKR in APPswePS1dE9 mice transiently prevents inflammation at 12 months of age but increases Aβ42 levels in the late stages of the Alzheimer’s disease
Couturier J, Paccalin M, Lafay-Chebassier C, Chalon S, Ingrand I, Pinguet J, Pontcharraud R, Guillard O, Fauconneau B and Page G
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00091]


Hippocampal BDNF Expression in a Tau Transgenic Mouse Model
Burnouf S, Belarbi K, Troquier L, Derisbourg M, Demeyer D, Leboucher A, Laurent C, Hamdane M, Buee L and Blum D
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00092]


UBQ-8i polymorphism is not an independent risk factor for mild cognitive impairment and Alzheimer’s disease in APOE-4 carriers
Elcoroaristizabal Martín X, Fernández Martínez M, Gamarra Fernandez D, Gómez Busto F, Galdos Alcelay L, Calzada Ferreras MJ, Castro Flores J and de Pancorbo M
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00093]


Targeting phospho-Ser422 by active Tau immunotherapy in the THY-Tau22 mouse model: a suitable therapeutic approach
Troquier L, Caillierez R, Burnouf S, Fernandez-Gomez FJ, Grosjean M-J, Zommer N, Sergeant N, Schraen-Maschke S, Blum D and Buee L
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00094]


Roles of Glycogen synthase kinase 3 in Alzheimer’s disease
Cai Z, Zhao Y and Zhao B
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00095]


In vivo uptake of β-amyloid by non-plaque associated microglia
Hawkes CA, Deng L, Fenili D, Nitz M and McLaurin J
[Abstract] [Purchase Article] [BSP/CAR/E-Pub/00096]


Lifestyle and Genetic Contributions to Cognitive Decline and Hippocampal Structure and Function in Healthy Aging
Woodard JL, Sugarman MA, Nielson KA, Smith JC, Seidenberg M, Durgerian S, Butts A, Hantke N, Lancaster M, Matthews MA and Rao SM
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00097]


Relationship between Inflammatory Mediators, Aβ Levels and APOE Genotype in Alzheimer’s Disease
Reale M, Kamal MA , Velluto L, Gambi D, Di Nicola M and Greig NH
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00098]


Reviewing the Role of Donepezil in the Treatment of Alzheimer’s Disease
Doody RS, Cummings JL and Farlow MR
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00099]


Effects of Atorvastatin on Cerebral Blood Flow in Middle-Aged Adults at Risk for Alzheimer’s Disease: A Pilot Study
Carlsson CM, Xu G, Wen Z,  Barnet JH, Blazel HM, Chappell RJ, Stein JH, Asthana S, Sager MA, Alsop DC, Rowley HA, Fain SB and Johnson SC
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00100]


Measuring Alzheimer disease progression with transition probabilities: Estimates from NACC-UDS
Spackman DE, Kadiyala S, Neumann PJ, Veenstra DL and Sullivan SD
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00101]


Ginsenoside Rg1 attenuates oligomeric Aβ_1-42-induced mitochondrial dysfunction 
Huang T, Fang F, Chen L, Zhu Y, Zhang J, Chen X and Yan SS
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00102]


PSEN1 Promoter Demethylation in Hyperhomocysteinemic TgCRND8 Mice is the Culprit,
not the Consequence
Fuso A, Cavallaro RA, Nicolia V and Scarpa S
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00103]


Age-related increase in levels of 5-hydroxymethylcytosine in mouse hippocampus is prevented by caloric restriction
Chouliaras L, van den Hove DLA, Kenis G, Keitel S, Hof PR, van Os J, Steinbusch HWM, Schmitz C and Rutten BPF
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00104]


The role of 5-hydroxymethylcytosine in aging and Alzheimer’s disease: current status and prospects for future studies
van den Hove DLA, Chouliaras L and Rutten BPF
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00105]


DNMT3B promoter polymorphisms and risk of late onset Alzheimer’s disease
Coppedè F, Zitarosa MT, Migheli F, Lo Gerfo A, Bagnoli S, Dardano A, Nacmias B, Mancuso M, Monzani F, Siciliano G, Sorbi S and Migliore L
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00106]


Alzheimer’s Disease and Environmental Exposure to Lead: The Epidemiologic Evidence and Potential Role of Epigenetics
Bakulski KM, Rozek LS, Dolinoy DC, Paulson HL and Hu H
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00107]


Alzheimer’s disease biomarkers and epigenetic intermediates following exposure to
Pb in vitro
Bihaqi SW and Zawia NH
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00108]


Lys²⁰³ and Lys³⁸² are essential for the proteasomal degradation of BACE1
Wang R, Ying Z, Zhao J, Zhang Y, Wang R, Lu H, Deng Y, Song W and Qing H
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00109]


The Role of TMP21 in Trafficking and Amyloid-β Precursor Protein (APP) Processing in Alzheimer's Disease
Bromley-Brits K and Song W
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00110]


Editorial: RIPpers at the Membrane – A brief history of APP Secretases, their Substraes and their Functions
Hartmann D
[BSP/CAR/E-Pub/00111]


EPA and DHA differentially affect in vitro inflammatory cytokine release by peripheral blood mononuclear cells from Alzheimer’s patients
Serini S, Bizzarro A, Piccioni  E, Fasano E, Rossi C, Lauria A, Cittadini ARM, Masullo C and Calviello G
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00112]


Dementia after Age 75: Survival in Different Severity Stages and Years of Life Lost
Rizzuto D, Bellocco R, Kivipelto M, Clerici F, Wimo A and Fratiglioni L
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00113]


The role of ER stress-induced apoptosis in neurodegeneration
Stefani IC, Wright D, Polizzi KM and Kontoravdi C
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00114]

Computer Based Classification of MR Scans in First Time Applicant Alzheimer Patients
Fatma Polat F , Demirel SO, Kitis O, Simsek F, Haznedaroglu  DI, Coburn K, Kumral E and Gonul AS
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00115]


PP2A and Alzheimer Disease
Torrent L and Ferrer I
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00116]


Do epigenetic pathways initiate late onset Alzheimer disease (LOAD): towards a new paradigm
Bihaqi SW, Schumacher A, Maloney B, Lahiri DK and Zawia NH
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00117]


Applying Epigenetics to Alzheimer’s Disease via the Latent Early–life Associated Regulation (LEARn) Model
Maloney B, Sambamurti K,  Zawia N and Lahiri DK
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00118]


Hippocampal Morphology and Autobiographic Memory in Mild Cognitive Impairment and Alzheimer’s Disease
Thomann PA, Seidl U, Brinkmann J, Hirjak D, Traeger T, Wolf RC, Essig M and Schröder J
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00119]


Editorial: Epigenetics: A paradigm shift in understanding Alzheimer’s Disease
Zawia NH and Lahiri DK
[BSP/CAR/E-Pub/00120]


Adult Changes in Thought Study: Dementia is an Individually Varying Convergent Syndrome with Prevalent Clinically Silent Diseases that may be Modified by Some Commonly Used Therapeutics
Montine TJ, Sonnen JA, Montine KS, Crane PK and Larson EB
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00121]


Overview and Findings from the Religious Orders Study
Bennett DA, Schneider JA, Arvanitakis Z and Wilson RS
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00122]


University of Kentucky Sanders-Brown Healthy Brain Aging Volunteers: Donor Characteristics, Procedures, and Neuropathology
Schmitt FA, Nelson PT, Abner E, Scheff S, Jicha GA, Smith C, Cooper G, Mendiondo M, Danner DD, Van Eldik LJ, Caban-Holt A, Lovell MA and Kryscio RJ
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00123]


A Population-Based Clinicopathological Study in the Oldest-Old: The 90+ Study
Corrada MM, Berlau DJ and Kawas CH
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00124]


Neuropathological correlates of falling in the CC75C population-based sample of the older old
Richardson K, Hunter S, Dening T, Xuereb JH, Matthews FE, Brayne C and Fleming J
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00125]


The Framingham Brain Donation Program: Neuropathology Along The Cognitive Continuum
Au R, Seshadri S, Knox K, Beiser A, Himali JJ, Cabral HJ, Auerbach S, Green RC, Wolf PA and McKee AC
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00126]


The Honolulu-Asia Aging Study: Epidemiologic and Neuropathologic Research on Cognitive Impairment
Gelber RP, Launer LJ and White LR
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00127]


Overview and Findings From the Rush Memory and Aging Project
Bennett DA, Schneider JA, Buchman AS, Barnes LL and Wilson RS
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00128]


The Minority Aging Research Study: Ongoing Efforts to Obtain Brain Donation in African Americans without Dementia
Barnes LL, Shah RC, Aggarwal NT, Bennett DA and Schneider JA
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00129]


The Nun Study: Risk Factors for Pathology and Clinical-pathologic Correlations
Morimer JA
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00130]


The Neuropathology of Vascular Disease in the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS)
Richardson K, Stephan BCM, Ince PG, Brayne C, Matthews FE and Esiri MM
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00131]


Analysis of Copy Number Variation in Alzheimer's Disease: the NIA-LOAD/NCRAD Family Study
Swaminathan S, Shen L, Kim S, Inlow M, West JD, Faber KM, Foroud T, Mayeux R and Saykin AJ
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00132]


Pretreatment with memantine prevents Alzheimer-like alterations induced
by intrahippocampal okadaic acid administration in rats
Zimmer ER, Kalinine E, Haas CB, Torrez VR, Souza DO, Muller AP and Portela LV
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00133]


Chronic infusion of amyloid-β peptide and sustained attention altered α 7 nicotinic receptor density in the rat brain
Viel TA, Caetano AL, Albuquerque MS, Araujo MS and Buck  HS
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00134]


Multi-target inhibitors for proteins associated with Alzheimer: In silico discovery using fragment-based descriptors
Speck-Planche A, Kleandrova VV , Luan F, Natália M and Cordeiro DS
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00135]


Magnetic resonance imaging in Alzheimer’s disease: from diagnosis to monitoring treatment effect
Filippi M, Agosta F, Frisoni GB, De Stefano N, Bizzi A, Bozzali M, Falini A, Rocca MA, Sorbi S, Caltagirone C and Tedeschi G
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00136]


The Effects of Cognitive Speed of Processing Training among Older Adults with Psychometrically- Defined Mild Cognitive Impairment
Valdés EG, O’Connor ML and Edwards JD
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00137]



Abstracts


Disentangling the role of the tau gene locus in sporadic tauopathies
Vandrovcova J, Anaya F, Kay V, Lees A, Hardy J, de Silva R.
[Purchase Article] [PMID: 20704554 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00001]

Fibrillar aggregates of abnormally hyperphosphorylated tau protein are the major component of the pathological entities, including intraneuronal neurofibrillary tangles that define the broad class of late-onset neurodegenerative disorders called the tauopathies. Mutations in the tau gene (MAPT) causing familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) confirm that tau protein dysfunction could be a primary cause of neuronal loss. However, in the sporadic tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) where MAPT mutation is absent, common variation in MAPT that defines the H1 and H2 haplotype clades strongly influences disease risk. Surprisingly, this influence on risk extends to sporadic Parkinson’s disease (PD), traditionally not defined as a tauopathy. This review will focus on recent work aimed at elucidating the mechanistic basis of this haplotype-specific effect on disease risk, implicating elevated levels of MAPT expression, particularly via increased transcription and/or alterations in splicing. This conforms to an emerging picture of a shared mechanism that underlies the fundamental process(es) leading to neuronal death. Increased availability of the fibrillogenic protein substrates of the pathological aggregates that define several neurodegenerative proteopathies, eg α-synuclein in PD, β-amyloid in AD and tau in the tauopathies, contributes to causation and risk in the familial and sporadic forms of these disorders, respectively
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Chromosome 17 in FTLD: from MAPT Tau to Progranulin and back
Alberici A, Cosseddu M, Padovani A, Borroni B
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00002]

Frontotemporal Lobar degeneration (FTLD) is one of the most important neurodegenerative conditions, affecting in the presenium, but more recently recognized also in aged population. The strong genetic background, along with autopsy determinations prompted the identification of the two major genes associated to the disease: MAPT gene, and Progranulin (PGRN) gene. In this review, we highlighted the milestones of these discoveries, and their implication for the development of future therapeuthical approaches.
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Mitochondria: the common upstream driver of Abeta and Tau pathology in Alzheimer´s disease
Diana FF. Silva, Esteves AR, Oliveira CR, Cardoso SM
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00003]

Mitochondrial dysfunction has been widely implicated in the etiology of Alzheimer´s disease (AD). Evidence shows a mitochondrial-mediated impairment of autophagy that potentiates amyloid-β (Aβ) deposition. Accordingly, recent data obtained from AD models, in which mitochondrial alterations are a prominent feature, demonstrated abnormalities in microtubule network, involving tubulin and tau post-translational modifications. In this review we will discuss mitochondrial-regulated processes where mitochondrial malfunction is likely to start a sequence of events leading to sirtuin-2 activation, microtubule network breakdown, and impairment of the autophagic pathway. Because sirtuin-2 activity depends on cellular NAD+ availability, mitochondrial regulation of NAD+ levels may contribute to an increase in sirtuin-mediated tubulin deacetylation. A vicious cycle become installed which potentiates tau hyperphosphorylation, together with Aβ overproduction and deposition. Overall, targeting microtubule network constitutes a promising strategy for pharmacological therapy in AD.
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Biochemical Differentiation of Cholinesterases from  Normal and Alzheimer’s Disease Cortex
Ciro A, Park J, Burkhard G, Yan N, Geula C
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00004]

In Alzheimer’s disease, histochemically visualized cholinesterases with altered pH optimum for activity and inhibitable by indoleamines and the protease inhibitor bacitracin emerge in association with plaques and tangles. It has been suggested that these cholinesterases may participate in the pathologic process. However, it is not known whether the properties of cholinesterases observed in Alzheimer’s disease are due to requirements of histochemical procedures or actual biochemical properties of these enzymes. Using biochemical assays of acetylcholinesterase and butyrylcholinesterase activities, we demonstrate here that serotonin and bacitracin result in a significantly greater and dose-dependent inhibition of cholinesterases in Alzheimer’s disease cortex when compared with age-matched controls. In contrast, variations in pH did not distinguish cholinesterases in Alzheimer’s disease and control cortex. We also confirmed significant reduction of acetylcholinesterase activity in Alzheimer’s disease cortex and increased butyrylcholinesterase activity that only approached significance. We conclude that inhibition by indoleamines and bacitracin is a biochemical characteristic of a proportion of cholinesterases in Alzheimer’s disease that most likely represents the pool associated with plaques and tangles. Most of the available cholinesterase inhibitors are relatively incapable of inhibiting cholinesterases associated with plaques and tangles. The findings of the present investigation open the way for attempts to isolate cholinesterases associated with plaques and tangles and design or discovery of inhibitors specifically targeted to cholinesterases in these lesions.
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Aβ Oligomers Induce Glutamate Release from Hippocampal Neurons
Brito-Moreira J, Paula-Lima AC, Bomfim TR, Oliveira FB, Sepúlveda FJ, De Mello FG, Aguayo LG, Panizzutti R, Ferreira ST
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00005]

Soluble oligomers of the amyloid-β peptide (AβOs) accumulate in Alzheimer’s disease (AD) brain and have been implicated in mechanisms of pathogenesis. The neurotoxicity of AβOs appears to be, at least in part, due to dysregulation of glutamate signaling. Here, we show that AβOs promote extracellular accumulation of glutamate and d-serine, a co-agonist at glutamate receptors of the N-methyl-d-aspartate subtype (NMDARs), in hippocampal neuronal cultures. The increase in extracellular glutamate levels induced by AβOs was blocked by the sodium channel blocker tetrodotoxin (TTX), by the NMDAR blocker (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) and by removal of Ca²⁺ from the extracellular medium, indicating dependence on excitatory neuronal activity. AβOs enhanced both the release of pre-synaptic vesicles labeled by FM1-43 and spontaneous post-synaptic activity measured by whole-cell patch-clamp. Activation of inhibitory GABA_A receptors by taurine blocked the increase in extracellular glutamate levels, suggesting that selective pharmacological inhibition of neuronal activity can counteract the impact of AβOs on glutamate dyshomeostasis. Results reveal a novel mechanism by which Aβ oligomers promote abnormal release of glutamate in hippocampal neurons, which may contribute to dysregulation of excitatory signaling in the brain.
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Determination of spatial and temporal distribution of microglia by 230nm-high-resolution, high-throughput automated analysis reveals different amyloid plaque populations in an APP/PS1 mouse model of Alzheimer’s disease
Scheffler K, Stenzel J, Krohn M, Lange C, Hofrichter J, Schumacher T, Brüning T, Plath A-S, Walker L, Pahnke J
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00006]

One early and prominent pathologic feature of Alzheimer’s disease (AD) is the appearance of activated microglia in the vicinity of developing β-amyloid deposits. However, the precise role of microglia during the course of AD is still under discussion. Microglia have been reported to degrade and clear β-amyloid, but they also can exert deleterious effects due to overwhelming inflammatory reactions. Here, we demonstrate the occurrence of developing plaque populations with distinct amounts of associated microglia using time-dependent analyses of plaque morphology and the spatial distribution of microglia in an APP/PS1 mouse model. In addition to a population of larger plaques (>700μm²) that are occupied by a moderate contingent of microglial cells across the course of aging, a second type of small β-amyloid deposits develops (≤400μm²) in which the plaque core is enveloped by a relatively large number of microglia. Our analyses indicate that microglia are strongly activated early in the emergence of senile plaques, but that activation is diminished in the later stages of plaque evolution (>150 days).  These findings support the view that microglia serve to restrict the growth of senile plaques, and do so in a way that minimizes local inflammatory damage to other components of the brain.
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The potential dual effects of anesthetic isoflurane on Aβ-induced apoptosis
Xu Z,  Dong Y, Wu X, Zhang J, McAuliffe S, Pan C, Zhang Y, Ichinose F, Yue Y, Xie Z
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00007]

β-amyloid protein (Aβ)-induced neurotoxicity is the main component of Alzheimer’s disease (AD) neuropathogenesis. Inhalation anesthetics have long been considered to protect against neurotoxicity. However, recent research studies have suggested that the inhalation anesthetic isoflurane may promote neurotoxicity by inducing apoptosis and increasing Aβ levels. We therefore set out to determine whether isoflurane can induce dose- and time-dependent dual effects on Aβ-induced apoptosis: protection versus promotion. H4 human neuroglioma cells, primary neurons from naïve mice, and naïve mice were treated with Aβ and/or isoflurane, and levels of caspase-3 cleavage (activation), apoptosis, Bcl-2, Bax, and cytosolic calcium were determined. Here we show for the first time that the treatment with 2% isoflurane for six hours or 30 minutes potentiated, whereas the treatment with 0.5% isoflurane for six hours or 30 minutes attenuated, the Aβ-induced caspase-3 activation and apoptosis in vitro. Moreover, anesthesia with 1.4% isoflurane for two hours potentiated, whereas the anesthesia with 0.7% isoflurane for 30 minutes attenuated, the Aβ-induced caspase-3 activation in vivo. The high concentration isoflurane potentiated the Aβ-induced reduction in Bcl-2/Bax ratio and caused a robust elevation of cytosolic calcium levels. The low concentration isoflurane attenuated the Aβ-induced reduction in Bcl-2/Bax ratio and caused only a mild elevation of cytosolic calcium levels. These results suggest that isoflurane may have dual effects (protection or promotion) on Aβ-induced toxicity, which potentially act through the Bcl-2 family proteins and cytosolic calcium. These findings would lead to more systematic studies to determine the potential dual effects of anesthetics on AD-associated neurotoxicity.
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Editorial:
[BSP/CAR/E-Pub/00009]

The role of inflammatory processes in Alzheimer's disease (AD) represents an area of research of great significance to the clinical research; however, the relevance of inflammatory response remains intensively debated..  Early epidemiological studies have demonstrated quite convincingly that the prolonged use of NSAIDs consistently diminishes the incidence of AD. As a result, these clinical observations greatly enhanced interest in NSAIDs, and spurred efforts to elucidate the inflammatory and immunological mechanisms involved in the neuropathology of AD. Most importantly, these findings led to a number of prospective clinical trials using NSAIDS and other anti-inflammatory reagents. However, these trials yielded largely disappointing results. These negative findings could signify that we have not found the right biological target. Additionally, after the clinical diagnosis of AD, it may simply be too late to delay or reverse AD pathology with therapeutic intervention using NSAIDs. In either case, in-depth knowledge of the inflammatory and immunological processes which aggravate or ameliorate the neuropathology of AD is likely fundamental to establish future therapeutic opportunities. Current research efforts are rapidly gaining insight into the possible preclinical benefits of NSAIDs.

This Hot Topics issue of Current Alzheimer's Research intends to review many of the fundamental problems relating inflammatory processes with the Alzheimer's neuropathology. The individual contributions collated here thoroughly review the literature and address the most urgent questions by discussing observations made in molecular-cell systems, transgenic models and human post-mortem brain material, and relate these findings to the lessons derived from recent clinical trials. 

In closing I would like to thank Professor Debomoy K.  Lahiri, the Editor in Chief of Current Alzheimer's Research for so positively responding to my suggestion of a special issue on: "Pro-inflammatory processes in the Alzheimer’s Pathology". I am also gratified by the enthusiastic response and excellent contributions received for this issue. Special thanks are due to Piet Eikelenboom, Michael Heneka, Magdalena Sastre, Serge Rivest, Terrence Town and their excellent collaborators.  I trust their articles will be valuable to many researchers in the field of AD.

On a personal note, I profoundly enjoyed this experience in that I now know some very interesting colleagues whom I had known previously only by their publications. Finally, special thanks are due to my assistant, Maureen Driscoll, who was of invaluable help in collating materials and their editing, and incredible support from the staff of Current Alzheimer Research of Bentham.
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The AICD interacting protein DAB1 is up-regulated in Alzheimer frontal cortex brain samples and causes deregulation of proteins involved in gene expression changes
Müller T, Loosse C, Schrötter A, Schnabel A, Helling S, Egensperger R, Marcus K
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00010]

AICD is the intracellular subdomain of the amyloid precursor protein thought to play a pivotal role as a potential transcription factor that might be of relevance for the pathophysiology of Alzheimer’s disease. For its signal transduction potential AICD requires interacting proteins like FE65 and TIP60. However, many other proteins were described being able to bind to AICD. Here, we studied mRNA levels of AICD interacting proteins and found one of them (DAB1) strongly up-regulated in human post-mortem frontal cortex brain samples of AD patients. Subsequent cell culture experiments revealed that elevated DAB1 level results in the deregulation of the cellular proteome. We found the proliferation associated protein 2G4 as well as the guanine monophosphate synthetase (GMPS) significantly up-regulated in DAB1 over-expressing cells. Both proteins can be involved in cellular transcription processes supporting the hypothesis that DAB1 acts via modification of the AICD-dependent transcriptionally active complex.

Of note, expression of the three components of the putative transcription complex (AICD, FE65, and TIP60 (AFT)) also revealed deregulation of the GMPS protein in an opposite fashion. Our results point to a putative relevance of AICD-dependent mechanisms in AD, caused by protein abundance changes of AICD interacting proteins, as shown for DAB1 in this work.
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Chronic Psychosocial Stress Exacerbates Impairment of Synaptic Plasticity in β-Amyloid Rat Model of Alzheimer’s Disease: Prevention by Nicotine
Alkadhi KA, Alzoubi KH, Srivareerat M and Tran  TT
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00011]

Alzheimer’s disease (AD) is a degenerative disorder that leads to progressive, irreversible cognitive decline. It develops as a result of over-production and aggregation of β-amyloid (Aβ) peptides in the brain. We have recently shown that stress exacerbates, while nicotine prevents long-term memory impairment induced by β-Amyloid. In this study, we evaluated the effect of chronic psychosocial stress on synaptic plasticity (Late-phase long-term potentiation; L-LTP, and long-term depression; LTD) in the β-Amyloid rat model of AD, and the positive impact of chronic nicotine treatment. Chronic psychosocial stress was induced by an intruder method.  The Rat AD model was induced by 14-day i.c.v. osmotic pump infusion of a 1:1 mixture of 300 pmol/day Aβ1-40/Aβ1-42. The rats were treated with nicotine (2 mg/kg/day) for 6 weeks. In vivo electrophysiological recordings of L-LTP, and LTD in hippocampal area CA1 showed that chronic stress by itself did not affect L-LTP. However, it markedly aggravated the impairment of this response as well as LTD in Aβ-treated rats. The effects of Aβ and the combination of stress and Ab were totally prevented by chronic nicotine treatment. Immunoblot analysis revealed that stress and/or Aβ significantly increased the basal levels of calcineurin and prevented the expected L-LTP-induced increase in CREB phosphorylation, and CaMKIV levels. These effects were not seen in Aβ-infused rats chronically treated with nicotine. The changes in synaptic plasticity-related molecules may explain the effects of stress and/or chronic nicotine on L-LTP in Aβ animals.
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Voluntary running and environmental enrichment restores impaired hippocampal neurogenesis in a triple transgenic mouse model of Alzheimer’s disease
Rodríguez JJ, Noristani HN, Olabarria M, Fletcher J, Somerville TDD, Yeh  CY, Verkhratsky A
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00012]

Alzheimer’s disease (AD) affects memory and neurogenesis. Adult neurogenesis plays an important role in memory function and impaired neurogenesis contributes to cognitive deficits associated with AD. Increased physical/cognitive activity is associated with both reduced risk of dementia and increased neurogenesis. Previous attempts to restore hippocampal neurogenesis in transgenic mice by voluntary running (RUN) and environmental enrichment (ENR) provided controversial results due to lack of non-transgenic (non-Tg) control and inclusion of social isolation as “standard” housing environment. Here, we determine the effect of RUN and ENR upon hippocampal neurogenesis in a triple transgenic (3xTg-AD) mouse model of AD, which mimics AD pathology in humans. We used single and double immunohistochemistry to determine the area density of hippocampal proliferating cells, measured by the presence of phosphorylated Histone H3 (HH3), and their potential neuronal and glial phenotype by co-localizing the proliferating cells with the immature neuronal marker doublecortin (DCX), mature neuronal marker (NeuN) and specific astroglial marker (GFAP). Our results show that 3xTg-AD mice in control environment exhibit impaired hippocampal neurogenesis compared to non-Tg animals at 9 months of age. Exposure to RUN and ENR housing restores hippocampal neurogenesis in 3xTg-AD animals to non-Tg control levels. Differentiation into neurones and glial cells is affected neither by transgenic status nor by housing environment. These results suggest that hippocampus of 3xTg-AD animals maintains the potential for cellular plasticity. Increase in physical activity and/or cognitive experience enhances neurogenesis and provides a potential for stimulation of cognitive function in AD.
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Recent breakthroughs in the understanding of Frontotemporal Lobar Degeneration and its related disorders.
Borroni B
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00013]

At the end of the nineteenth century, Arnold Pick was the first to clinically describe frontotemporal lobar degeneration in several patients who presented aphasia, behavioral disturbances, atrophy of the frontal and temporal lobes, and argyrophilic inclusions (“Pick bodies”) [1]. In the following years, frontotemporal lobar degeneration was classified with several different neurodegenerative conditions that can be characterized by distinct pathological determinations, including “dementia lacking distinctive histology and “non-Pick lobar atrophy”. This collection of clinical symptoms presented within the Lund Manchester criteria allowed the recognition and diagnosis of this heterogeneous spectrum of neurodegenerative diseases [2]. Currently, the diagnostic criteria for frontotemporal lobar degeneration are clinically determined using the Neary and McKhann criteria [3, 4]. The Neary and McKhann criteria define different conditions, including [1] frontotemporal dementia, [2] progressive non-fluent aphasia, [3] semantic dementia, [4] corticobasal syndrome, [5] progressive supranuclear palsy, and [6] frontotemporal dementia with motor neuron disease. Clinical phenotypes are characterized by different neuropathological hallmarks, and three major frontotemporal lobar degeneration molecular classes have been currently described, which are composed of one of three major classes of abnormal cellular inclusions containing either tau, TAR DNA-binding protein of 43 kDa (TDP-43), or fused in sarcoma (FUS) proteins [5]. Frontotemporal lobar degeneration with tau-immunoreactive inclusions, i.e. FTLD-tau, has long been associated with diverse pathological subtypes, including Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, and others, all defined by recognizable neuronal and glial morphological tau inclusions [5]. In the same view, recent work has demonstrated a FTLD-TDP spectrum with four different molecular subtypes [6-8].

Along with neuropathological feature definition, one of the major contributions to the understanding of frontotemporal lobar degeneration has been gained through scientific discoveries resulting from genetic studies. In the last few years, neuropathology and genetics have split and lumped the disease into biological and clinical phenotypes.

The present issue of Current Alzheimer Research provides a synthesis of the recent genetics and biology breakthroughs associated with frontotemporal lobar degeneration by revisiting its clinical phenotypes. First, Andrew Kertesz provides an overview of Pick’s Complex, and reviews the overlap of the different clinical symptoms defined by this syndrome [9]. In fact, it has been widely demonstrated that the clinical phenotypes may switch from one to another during disease course, some authors using the term “Pick’s disease” to group the different variants under the same label.
However, a clear-cut distinction might be obtained on the basis of genetic trait. For example, Antonella Alberici and colleagues present clinical and neuroimaging features associated with frontotemporal lobar degeneration primarily caused by two genes involved in disease pathogenesis [10]. These genes include microtuble associated protein Tau (MAPT) and progranulin (PGRN), the most frequent causes of autosomal dominant inherited disorder, that lead to either FTLD-tau positive or FTLD-TDP positive disorder, respectively [11-13]. The authors discuss common and distinctive features of the two diseases and the possibility to identify them on clinical grounds.

Emanuele Buratti’s group then explores the complex molecular pathways that link different proteins that are found as deposits in FTLD-tau negative pathology [14]. As described above, these deposits are now associated with TDP-43 and FUS inclusions [15, 16], two RNA-binding proteins already known to play a role in several cellular processes such as transcription, pre-mRNA splicing, and mRNA stability. The detailed knowledge of the gain- or loss-of-function mechanisms mediated by alterations in these newly identified key proteins in the neuronal environment may provide novel therapeutic strategies for the treatment of these diseases.

Finally, the genetics of rare cases of frontotemporal lobar degeneration, i.e.  charged multi-vescicular dody protein (CHMP2B) and valosin-containing protein (VCP) mutations, are discussed by Adrian Isaacs and colleagues [17] and Conrad C. Weihl [18], respectively. The possibility to study the underscored mechanisms of these rare disorders will allow to know the molecular pathways involved in frontotemporal lobar degeneration and to target new pathogenetic determinants.

The second section of the present issue is dedicated to clinical aspects and different phenotypes associated with the frontotemporal lobar degeneration spectrum. In fact, if neuropathological and genetic features are detrimental in molecular diagnosis, the definition of clinical phenotypes are mandatory for prognostic purposes. As reviewed by Davies Rhys and colleagues [19], the pattern of lobar atrophy may have clinical and prognostic implications in behavioural variant frontotemporal dementia. The authors pointed out that lobar atrophy seems to be a key observation in defining frontotemporal lobar degeneration, and phenocopies should be taken into consideration in light of future clinical and therapeutic trials. Additionally, Jonathan Rohrer and colleagues [20] present an overview of the recent advancements in the language variants of frontotemporal lobar degeneration spectrum, namely the Primary Progressive Aphasias. These represent an heterogeneous neuropathological entity, and the authors discuss the current and future biomarkers such as clinical and neuropsychological data, neuroimaging, blood and CSF markersthat that may help make a pathological diagnosis in life.

Finally, two syndromes sharing neuropathological and genetic background with frontotemporal lobar degeneration, i.e. Progressive Supranuclear Palsy and frontotemporal dementia with motor neuron disease, are reviewed by John van Swieten and colleagues [21] and by Raffaele Ferrari and colleagues [22], respectively. Indeed, there is growing body of evidence that these syndromes are more frequent than previously thought.

In the field of neurodegenerative dementias, recent years have witnessed a dramatic improvement in the knowledge of the underlying mechanisms that contribute to frontotemporal lobar degeneration. However, many aspects of frontotemporal lobar degeneration remain unknown. By applying an integrative approach combining genetic, biological, neuroimaging and clinical aspects, new avenues of research will pave the way to a better understanding of its pathogenesis and identifiction of targets for pharmacological development and intervention.
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The Overlapping Syndromes of the Pick Complex
Kertesz A
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00014]

A significant expansion of knowledge in the last few years, especially in the molecular biology of frontotemporal dementia (FTD) is summarized. This condition, formerly known as Pick’s disease and considered rare, is estimated to be 12-15% of all dementias and 30-50% early onset ones. The clinical picture is protean, mainly a behavioural and language impairment, but the extrapyramidal syndromes of CBD and PSP are often seen and conversely FTD and progressive aphasia often has motor symptoms, including ALS . These seemingly different presentations converge, as one or other areas in the brain are affected. Our experience with FTD in a clinical cohort, with high rate of autopsy confirmation is presented. Less than half of the cases are tauopathies, the majority has been discovered to have a TDP-43 and most recently a FUS proteinopathy, shared with ALS, opening potential opportunities for pharmacological approaches to treatment. Tau and progranulin mutations on Ch-17 and some others, point to molecular mechanisms. A glossary is provided to navigate the complex terminology.
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Effect of Cholinergic Stimulation in Early Alzheimer’s Disease – Functional Imaging During a Recognition Memory Task
Miettinen PS, Pihlajamäki M, Jauhiainen AM, Tarkka IM, Gröhn H, Niskanen E, Hänninen T, Vanninen R, Soininen H
[FULL-TEXT INQUIRY] [PMID: 21592058 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00015]

Treatment of Alzheimer’s disease (AD) with acetylcholinesterase inhibitors (AChEI) enhances cholinergic activity and alleviates clinical symptoms. In the present functional magnetic resonance imaging (fMRI) study, we investigated the effect of the AChEI rivastigmine on cognitive function and brain activation patterns during a face recognition memory task. Twenty patients with newly-diagnosed mild AD were administered a single oral dose of placebo, a single dose of rivastigmine (acute), and twice-daily treatment with rivastigmine for 4 weeks (chronic). After each treatment, the patients underwent a facial recognition task during fMRI. The prefrontal areas known to be involved in face recognition memory processing demonstrated greater fMRI activity in both the acute and chronic rivastigmine conditions compared to the placebo condition. In the same brain areas, differences in both fMRI activation at the map level and regional fMRI signal intensity measures between the placebo and chronic treatment conditions correlated negatively with the Mini-Mental State Examination score. In the chronic rivastigmine condition, - patients with better preserved cognitive abilities demonstrated less enhanced prefrontal activity, whereas patients with poorer cognition showed greater prefrontal activity. These findings suggest that the prefrontal attention/working memory systems are already impaired in the early stages of AD and that the effect of cholinergic medication in the brain areas involved in recognition memory, i.e., increased or decreased fMRI activation patterns, depends on the severity of the disease. These findings also suggest the importance of early AChEI treatment in the course of AD, at the point when there is still some cognitive reserve available and the therapy has the highest potential efficacy.
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Mobilization and redistribution of default mode network from resting state to task state in amnestic mild cognitive impairment
Bai F, Watson DR, Shi Y, Yuan Y, Yu H, Zhang Z
[FULL-TEXT INQUIRY] [PMID: 21592057 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00016]

Brain task-negative networks (default mode network, DMN) and task-positive networks appear to operate largely in opposition, such that task-negative networks show activation during resting states, whilst task-positive networks are deactivated with the reverse being true during goal-oriented behavior. Altered DMN and task-positive network activity has been observed in amnestic mild cognitive impairment (aMCI) subjects. However, no study has directly linked the patterns of between-state differences in the same aMCI cohort regarding these two types of functional networks. The spatial and temporal characteristics of intrinsic, low frequency BOLD signal fluctuations both during resting state and episodic memory fMRI task were assessed in 28 aMCI subjects and 23 matched healthy controls, using a posterior cingulate cortex-based temporal correlation analysis. aMCI subjects showed impaired attenuation in the DMN between rest and task state, and greater cognitive impairment was associated with decreased ability to attenuate DMN during task engagement. Moreover, more redistributed resource from DMN appeared to be required in aMCI to maintain the similar task performance possibly to offset their inability to engage task-positive networks. In order to complete a given task, mobilized and redistributed resources of DMN appeared to replace task-positive network function to some degrees in aMCI subjects. This may represent an inability to control the switching of functional modes between these types of network.
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Follow-up Study of Olfactory Deficits, Cognitive Function, and Volume Loss of Medial Temporal Lobe Structures in Patients with Mild Cognitive Impairment
Lojkowska W, Sawicka B, Gugala M, Sienkiewicz-Jarosz H, Bochynska A, Scinska A, Korkosz A, Lojek E, Ryglewicz D
[FULL-TEXT INQUIRY] [PMID: 21592056 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00017]

Background: At 3 years after diagnosis, the risk of Alzheimer disease (AD) for patients with mild cognitive impairment (MCI) is estimated to be 18% to 30%. To improve treatment of patients at high dementia risk there is a need for a better prediction of the risk for transition from MCI to AD. Hypothetical predictors of conversion form MCI to AD  are Olfactory deficits and volumetric reduction of medial temporal lobe structures. The primary aim of this study was to evaluate whether investigations of odor deficits in MCI combined with neuropsychological tests as well as MRI examination can improve prediction of the development of dementia.

Methods: Changes in olfactory functions, cognitive functions, and volume of medial temporal lobe structures (hippocampus, parahippocampal gyrus, and amygdala) were evaluated in a 24-month follow-up study in 49 MCI patients and 33 controls.

Results: In the MCI group, deterioration of odor identification, decline of cognitive functions, and reduction of hippocampus volume were mutually correlated. A prediction of strong cognitive functions deterioration based on poor performance in Olfactory Identification tests or cognitive functions shows sensitivity of 57% and 44%, respectively, and specificity of 88% and 89%, respectively, while a combined tests where as a criterion is poor olfactory identification performance AND poor results of neuropsychological tests shows a sensitivity of 100% and specificity of 84%. There is correlation between the results of Olfactory Identification tests at baseline and deterioration of cognitive functions at follow up. Odor identification threshold did not appear to be a dementia predictor. There is also a correlation of progress of cognitive function deterioration, odour identification deterioration, and decrease of volume of the hippocampus.

Conclusions: Odor identification tests combined with neuropsychological tests permit to improve prediction of rapid deterioration of cognitive functions and MCI to dementia conversion. A follow up study of hippocampus volume may further increase prediction accuracy.
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Anti-β-amyloid Immunotherapy for Alzheimer’s Disease: Focus on Bapineuzumab
Panza F, Frisardi V, Imbimbo BP, Seripa D, Paris F, Santamato A, D’Onofrio G, Logroscino G, Pilotto A, Solfrizzi V
[Purchase Article] [PMID: 21592055 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00018]

Recent advances in our understanding of the neurobiology of Alzheimer’s disease (AD) have led to the development of putative disease-modifying treatments. The most revolutionary of these approaches consists in the removal of brain β-amyloid (Aβ) via anti-Aβ antibodies. Brain imaging and neuropathological studies have shown the ability of both active and passive anti-Aβ immunotherapies of clearing Aβ deposits from the brain of the AD patients. An active anti-Aβ vaccine preparation, AN1792, has been used in AD patients with some clues of clinical efficacy but causing meningoencephalitis in about 6% of patients and it has been abandoned. Several second-generation active Aβ vaccines and passive Aβ immunotherapies have been developed and are under clinical investigation with the aim of accelerating Aβ clearance from the brain of the AD patients.  The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Aβ monoclonal antibodies, that has been tested in two Phase II trials, demonstrating to reduce Aβ burden in the brain of AD patients. However, the preliminary cognitive efficacy of bapineuzumab appears uncertain. The occurrence of vasogenic edema, especially in apolipoprotein E e4 carriers, may limit its clinical use and have led to abandon the highest dose of the drug (2 mg/kg). The results of four ongoing large Phase III trials on bapineuzumab will tell us if passive anti-Aβ immunization is able to alter the course if this devastating disease.
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Dysregulated NF-κB pathway in peripheral mononuclear cells of Alzheimer’s disease patients
Ascolani A, Balestrieri E, Minutolo A, Mosti S, Spalletta G, Bramanti P, Mastino A, Caltagirone C, Macchi B
[FULL-TEXT INQUIRY] [PMID: 21592054 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00019]

Diagnosis and therapeutic strategies in Alzheimer's disease (AD) might greatly benefit of the present  multidisciplinary approach for studying the molecular pathogenesis of the disorder. Gene expression profile at peripheral level could be a promising tool for pathogenic studies as well as for early diagnosis of AD. A dysregulated inflammatory response, as well as other systemic disorders, have been described in AD. Therefore, we investigated the  expression, at peripheral level, of a number of genes involved in the inflammatory, oxidative stress and proliferative response of a well defined, small cohort of sporadic AD patients. Firstly, the mRNA expression of inflammatory, stress and proliferation/differentiation genes were evaluated, using SuperArray, in mitogen-stimulated peripheral blood mononuclear cells (PBMC) from a group of 12 well-characterized, sporadic AD patients with various levels of dementia, by comparison with aged-matched controls. Real-time RT-PCR confirmed the trend of alteration in 16 genes out of the 36 supposed to be dysregulated in AD patients, by the preliminary screening. The expression level of the NFKB1(p105/50Kd) gene was significantly higher in AD with respect to adult age-matched controls (AA) and was related to the Mini-Mental State Examination (MMSE) score of the same patients. In addition,  the expression of various NF-κB target genes and of both NF-κBp50 and NF-κBp65 DNA-binding activity were increased in PBMC from AD patients in comparison with those from AA. Our results suggest that NF-κB activation at peripheral blood cell level could be a potential new hallmark of AD progression and sustain a rationale to more deeply investigate the therapeutic potential of specific NF-κB inhibitors in AD.
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Amyloid ß Peptide Levels Increase in Brain of AßPP Swedish Mice after Exposure to Chlorpyrifos
Salazar JG, Ribes D, Cabré M, Domingo JL, Sanchez-Santed F, Colomina MT
[FULL-TEXT INQUIRY] [PMID: 21592053 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00020]

Chlorpyrifos (CPF) is an organophosphate pesticide widely used in intensive agriculture. Various studies have demonstrated delayed neurotoxic effects in adult mammals after acute CPF exposure. This pesticide induces oxidative stress and neuronal damage, which suggests a possible relationship between CPF exposure and Alzheimer’s disease (AD). In the present study, we examined in a mice model of AD, long-term changes in the behavior and brain levels of amyloid ß after acute CPF exposure. Fifty mg/kg of CPF were subcutaneously injected to Tg2576 (Tg) mice carrying the Swedish amyloid-ß protein precursor (AßPP) mutation for AD. General status, body weight, acetyl cholinesterase (AChE) inhibition, and behavioral changes were assessed. Amyloid ß fragment (1-40 and 1-42) levels were also measured in the cortical and hippocampal brain regions. A significant and transient decrease in body weight was observed 72 hr after treatment, while no autonomic effects were noted. Motor activity was decreased in Tg mice seven months after CPF treatment. Acquisition learning in a water maze task was not affected, but retention was ameliorated in CPF-exposed Tg mice. Amyloid ß levels increased in the brains of treated Tg mice eight months after CPF exposure. The results of this study show that some behavioral changes persisted or emerged months after acute CPF exposure, while amyloid ß levels increased. These findings raise concern about the risk of developing neurodegenerative diseases following moderate exposure to CPF in vulnerable subjects.
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Transgenic Mice as a Model for Alzheimer’s Disease
Lithner CU, Hedberg MM, Nordberg A
[FULL-TEXT INQUIRY] [PMID: 21592052 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00021]

During the last few decades, numerous stable transgenic mouse strains have been developed in order to mimic a range of Alzheimer’s disease (AD)-related pathologies. Although none of the models fully replicates the human disease, the models have been a key feature in translational research, providing significant insights into the pathophysiology of AD. They have also been widely used in the preclinical testing of potential therapies. The choice of transgenic mouse model, as well as the stage of Aβ pathology, significantly contributes to the outcome of the studies. Therefore, it is important to combine studies in different transgenic mouse models and detailed in vitro experiments to obtain a complete understanding of the origin of the disease, the actual sequences of early pathological events as well as being able to evaluate the effects of new drugs in the treatment of AD.
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Aβ(1-42) Aggregates into non-Toxic Amyloid Assemblies in the Presence of the Natural Polyphenol Oleuropein Aglycon
Rigacci S, Guidotti V, Bucciantini M, Nichino D, Relini A, Berti A, Stefani M
[FULL-TEXT INQUIRY] [PMID: 21592051 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00022]

Amyloid aggregation starts with the initial misfolding of peptide/protein precursors, with subsequent structural rearrangement into oligomers and protofibrils; the latter eventually organize into fibrils with shared basic structural features, found deposited in amyloid diseases. Mounting evidence indicates early oligomers as the most toxic amyloid species; accordingly, the search of inhibitors of their growth is considered a promising target to prevent amyloid toxicity. We recently showed that oleuropein aglycon, a polyphenol abundant in the extra virgin olive oil, interferes with the aggregation of amylin (involved in type-2 diabetes), eliminating its cytotoxicity. Here we report that oleuropein aglycon also hinders amyloid aggregation of Aβ(1-42) and its cytotoxicity, suggesting a general effect of such polyphenol. In particular, by using a wide panel of different spectroscopic, immunologic, cell viability and imaging techniques we provide a more detailed description of Aβ(1-42) structural modifications arising in the presence of the inhibitor and the resulting cytotoxicity. We here report that the polyphenol eliminates the appearance of early toxic oligomers favouring the formation of stable harmless protofibrils, structurally different from the typical Aβ(1-42) fibrils. We also show that oleuropein aglycon is maximally effective when is present at the beginning of the aggregation process; furthermore, when added to pre-formed fibrils, it does not induce the release of toxic oligomers but, rather, neutralizes any residual toxicity arising from the residual presence of traces of soluble oligomers and other toxic aggregates. The possible use of this polyphenol as anti-aggregation molecule is discussed in the light of these data.
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Left Anterior Temporal Lobe Sustains Naming in Alzheimer's Dementia and Mild Cognitive Impairment
Frings L, Klöppel S, Teipel S, Peters O, Frölich L, Pantel J, Schröder J, Gertz H-J, Arlt S, Heuser I, Kornhuber J, Wiltfang J, Maier W, Jessen F, Hampel H, Hüll M
[FULL-TEXT INQUIRY] [PMID: 21592050 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00023]

Cognitive decline in degenerative dementia is paralleled by progressive brain atrophy, with the localization of atrophy reflecting specific cognitive impairment. Confrontation naming deficits are frequently observed in dementia across etiologies. In this study we aimed to identify the brain regions underlying this deficit.

In patients with clinically diagnosed dementia or mild cognitive impairment (MCI) we investigated the relationship between gray matter volume (GMV) and performance on a standardized confrontation naming test. 268 patients with one of three probable etiologies were included: Alzheimer's Dementia (AD), AD with signs of cerebrovascular pathology, and frontotemporal dementia. Applying voxel-based morphometry using a diffeomorphic registration algorithm we contrasted GMV of patients performing within the normal range with those of patients with pathological performance. Further, differential effects of gray matter atrophy on impaired performance in AD versus MCI of AD type were investigated.

Results revealed significantly reduced GMV in the left anterior temporal lobe (ATL) in pathological performers compared to normal performers. The subgroup analysis confined to MCI of AD type and AD patients confirmed this relationship. While left ATL atrophy is known to be implicated in naming deficits in semantic dementia, our data confirm the same in AD and MCI of AD type.
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Effects of Coenzyme Q and Creatine Supplementation on Brain Energy Metabolism in Rats Exposed to Chronic Cerebral Hypoperfusion
Horecky J, Gvozdjáková A, Kucharská J, Obrenovich ME, Palacios HH, Li Y, Vancová O, Aliev G
[FULL-TEXT INQUIRY] [PMID: 21592049 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00024]

It is known that oxidative stress and mitochondrial dysfunction both play an important role in animal models of brain ischemia.  The present study was undertaken to test whether oral supplementation of coenzyme Q10 (ubiquinone) or creatine citrate could protect against brain ischemia-induced mitochondrial damage in the rats model.  Brain ischemia was induced for 50 minutes with three-vessel occlusion (3-VO).  Coenzyme Q10 was administered for 30 days before the ischemic event and coenzyme Q10 or creatine citrate for 30 days post-ischemia. Moreover, the concentrations of coenzyme Q10 and α-, γ- tocopherols as well as the formation of thiobarbituric acid reactive substances (TBARS) were measured in brain mitochondria and in plasma.  Transient hypoperfusion revealed significant impairment in brain energy metabolism as detected by mitochondrial oxidative phosphorylation as well as decreased concentrations of brain and plasma endogenous antioxidants and increased formation of TBARS in plasma.  When compared with the ischemic group, supplementation of coenzyme Q10 was ineffective as a preventive agent.  However, the positive effect of therapeutic coenzyme Q10 supplementation was supported by the oxygen consumption values (p<0.05) and ATP production (p<0.05) in brain mitochondria, as well as by increased concentration of coenzyme Q9 (p<0.05) and concentration of α-tocopherol (p<0.05) in brain mitochondria and by increased concentration of α-tocopherol (p<0.05) and β-tocopherol in plasma.  This suggests that coenzyme Q10 therapy involves resistance to oxidative stress and improved brain bioenergetics, when supplemented during reperfusion after ischemic brain injury.
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Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: Two phase 3 studies
Harrington C, Sawchak S, Chiang C, Davies J, Donovan C, Saunders AM, Irizarry M, Jeter B, Zvartau-Hind M, van Dyck CH, Gold M
[Purchase Article] [PMID: 21592048 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00025]

Introduction: Two phase 3 studies evaluated the efficacy and safety of rosiglitazone (RSG), a type 2 diabetes treatment, in an extended release (RSG XR) form as adjunctive therapy to ongoing acetylcholine esterase inhibitor (AChEI) treatment in AD (REFLECT-2, adjunctive to donepezil; REFLECT-3, to any AChEI). An open-label extension study (REFLECT-4) assessed RSG XR long-term safety.

Methods: In these two double-blind, placebo-controlled studies, subjects with mild-to-moderate probable AD were randomized within 2 apolipoprotein E (APOE) allelic strata (APOE ε4-positive, APOE ε4-negative) to once daily placebo, 2 mg RSG XR, or 8 mg RSG XR for 48 weeks (REFLECT-2, N=1,496; REFLECT-3, N=1,485). Co-primary efficacy endpoints were change from baseline in Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) scores at week 48. Three populations were analyzed: APOE4-negative, all subjects except APOE ε4 homozygotes, and the full intent-to-treat population.

Results: No statistically or clinically relevant differences between treatment groups were observed on the a priori primary endpoints in REFLECT-2 or REFLECT-3. Edema was the most frequent adverse event with RSG in each study (14% and 19%, respectively, at 8 mg RSG XR).

Conclusions: No evidence of statistically or clinically significant efficacy in cognition or global function was detected for 2 mg or 8 mg RSG XR as adjunctive therapy to ongoing AChEIs. There was no evidence of an interaction between treatment and APOE status. Safety and tolerability of RSG XR was consistent with the known profile of rosiglitazone.
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Mild Cognitive Impairment (MCI) – the novel trend of targeting Alzheimer`s disease in its early stages - Methodological considerations.
Pater C
[FULL-TEXT INQUIRY] [PMID: 21592047 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00026]

While much uncertainty exists in the estimates of the global burden of Alzheimer’s disease and about the potential impact of various interventions, there is a widespread acceptance of the fact that the steady increase in the incidence and prevalence of the condition worldwide is becoming a massive public health problem as well as a huge economic burden for all healthcare systems and societies. These heavy demands are further compounded by the poor quality of life of the affected individuals, of their families and of their caregivers.

The epidemic proportion of Alzheimer’s disease has triggered relentless attempts for development of treatment approaches during the past two decades by a multitude of pharmaceuticals and biotech companies. Commercial development of the acetylcholinesterase inhibitors has, until recently, virtually dominated the field and, although efficacy has been demonstrated for five different products, the long-term clinical results suggested that alternate approaches were warranted.

Disease modifying strategies targeting the β-amyloid plaques (e.g., decreasing β-amyloid formation through β- and γ-secretase inhibition, diminishing β-amyloid aggregation through anti-aggregants or enhancement of β-amyloid clearance through active/passive immunization), targeting the neurofibrillary tangles through inhibition of tau protein hyperphosphorilation or, more recently, by increasing mitochondrial permeability, all these potential treatment modalities are facing major methodological challenges during the conduct of a myriad of clinical trials meant to bring the novel therapies to the market.

Failure of more than 400 products tested in more than 800 clinical trials to date, with many of these failures occurring in late stage development (phase III) have triggered a paradigm shift toward targeting of the early stages of cognitive deficiencies (mild cognitive impairment-MCI) and a refinement of the investigative methodologies.

The great heterogeneity of the disease entity itself (MCI) coupled with inadequate sensitivity, specificity and positive/negative predictive values of the many common diagnostic outcome scales, outcome measures, and of many of the currently used biomarkers expose the drug development professionals to the risk of methodological flaws rendering the products explored ineffective, while very expensive.
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Mechanisms of tau selfaggregation and neurotoxicity
Farías G, Cornejo A, Jiménez J, Guzmán L,  Maccioni RB
[FULL-TEXT INQUIRY] [PMID: 21605046 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00027]

Pathological tau protein aggregates can be found in brain of patients with some of the neurodegenerative diseases collectively known as tauopathies, which include Alzheimer’s disease (AD). Since tau post-translational modifications including phosphorylations, glycosylations, truncation and the subsequent aggregation in oligomers, paired helical filaments (PHFs) and neurofibrillary tangles (NFTs), correlate with cognitive impairment and neurodegeneration in AD, a pathogenic role for tau and its modifications has been raised.

Here we summarize the current status of knowledge about tau modifications under pathologic conditions and the evidence supporting neurotoxic – or neuroprotective – roles of the diverse forms of modified and aggregated tau. Finally, we analyze the structural and functional tau alterations found in different tauopathies and how these modifications are related to the pathophysiologic mechanisms of neurodegeneration.
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Pin1: a new outlook in Alzheimer Disease
Elena L, Massimo M, Alessandra B
[FULL-TEXT INQUIRY] [PMID: 21605045 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00028]

Neurodegenerative diseases termed Tauopathies, including Alzheimer disease, are characterized by the presence of intraneuronal neurofibrillary tangles (NFTs), composed by hyperphosphorylated protein Tau. Peptidyl-prolyl cis/trans isomerase Pin1 plays a pivotal role in the regulation of Tau phosphorylation/dephosphorylation state. Indeed, Pin1 specifically recognizes pThr231-Pro232 motif of Tau, catalyzes its isomerisation and, in dependence of the cellular environment, promotes its dephosphorylation by PP2A phosphatase: in the dephosphorylated state Tau is able to exert its physiological activity, promoting microtubules polymerization. However, Pin1 activity in Tauopathies in which Tau is mutated can be harmful, because the isomerase can accelerate progression of the disease.

Taking into account the complexity of pathways in which Pin1, under a strict regulation, exerts its biological functions, this isomerase can be consider a promising target in the improvement and design of new therapies against Tauopathies.
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Role of protein phosphatase 2A in Alzheimer’s Disease
Rudrabhatla P, Pant HC
[Purchase Article] [PMID: 21605044 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00029]

Alzheimer disease (AD) is the most common cause of dementia in adults. Aberrant hyperphosphorylation of microtubule associated protein Tau and neurofilament-M/H is one of the pathological hallmarks of AD. Most of the therapeutic strategies for treating AD are based on the inhibition of protein kinases such as glycogen synthase kinase-3β, cyclin-dependent kinase 5, and other Tau kinases. Here, we focus on protein phosphatase 2A (PP2A) as a key player in AD. PP2A expression and activity are downregulated in AD brain, contributing to the aberrant phosphorylation of Tau and NF proteins in AD. Recent data published from our lab as well as others on PP2A deregulation in AD is reviewed. The role of peptidyl prolyl isomerase Pin1 in regulation of PP2A mediated neurodegeneration is further analyzed.  Development of drugs for AD could be based on restoration of PP2A activity or targeting Pin1.
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Loss of medial septum cholinergic neurons in THY-Tau22 mouse model: what links with tau pathology?
Belarbi K, Burnouf S, Fernandez-Gomez F-J, Desmercières J, Troquier L, Brouillette J, Tsambou L, Grosjean M-E, Caillierez R, Demeyer D, Hamdane M, Schindowski K, Blum D, Buée L
[FULL-TEXT INQUIRY] [PMID: 21605043 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00030]

Alzheimer’s disease (AD) is a neurodegenerative disorder histologically defined by the cerebral accumulation of amyloid deposits and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Loss of basal forebrain cholinergic neurons is another hallmark of the disease thought to contribute to the cognitive dysfunctions. To this date, the mechanisms underlying cholinergic neurons degeneration remain uncertain. The present study aimed to investigate the relationship between neurofibrillary degeneration and cholinergic defects in AD using THY-Tau22 transgenic mouse model exhibiting a major hippocampal AD-like tau pathology and hyperphosphorylated tau species in the septohippocampal pathway. Here, we report that at a time THY-Tau22 mice display strong reference memory alterations, the retrograde transport of fluorogold through the septohippocampal pathway is altered. This impairment is associated with a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum. Analysis of nerve growth factor (NGF) levels supports an accumulation of the mature neurotrophin in the hippocampus of THY-Tau22 mice, consistent with a decrease of its uptake or retrograde transport by cholinergic terminals. Finally, our data strongly support that tau pathology could be instrumental in the cholinergic neuronal loss observed in AD.
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A Novel Perspective on Tau in Alzheimer Disease
Bonda DJ, Castellani RJ, Zhu X, Nunomura A, Lee H-G, Perry G, Smith MA
[Purchase Article] [PMID: 21605042 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00031]

Mainstream thinking is dominated by the notion that the aggregation of specific proteins within neurons, and their subsequent formation into cytoplasmic and extracellular lesions, directly elicits neuronal dysfunction and death. Current dogma, for example, maintains that phosphorylated tau protein, the major component of neurofibrillary tangles, is a central mediator of disease pathogenesis. In this article, we challenge this classic notion by proposing that tau phosphorylation represents a compensatory response mounted by neurons against oxidative stress that serves a protective function. This concept provides a better understanding of the mechanisms underlying disease pathophysiology and also provides a window for therapeutic intervention.
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Abl tyrosine kinase signaling: A new player in AD Tau pathology.
Estrada LD, Zanlungo SM, Alvarez AR
[FULL-TEXT INQUIRY] [PMID: 21605041 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00032]

Hyperphosphorylated tau is a cardinal feature of Alzheimer’s disease (AD) pathology. The deregulation of kinases that phosphorylate tau can alter normal tau-related processes, including microtubule dynamics, growth cones, and axonal transport, and induce the aggregation of tau in paired helical filaments. Here we discuss the possible roles of the Abl family of tyrosine kinases, which are essential regulators of cytoskeleton cellular signaling cascades, in AD tau pathology and how the physiological roles of Abl kinases could be connected with the cytoskeletal alterations induced by Aβ aggregates and AD progression.
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Molecular targets in the rational design of AD specific PET tracers:  tau or amyloid aggregates?
Rojo LE, Gaspar P, Maccioni RB
[FULL-TEXT INQUIRY] [PMID: 21605040 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00033]

A major limitation in finding therapeutic solutions for Alzheimer´s disease (AD) has been the lack of a reliable method for early diagnosis of this devastating disease. Besides the development of biomarkers in biological fluids of patients, the search for a pathology-specific neuroimaging tools is critical at the present stage in which almost 30 million people suffer this disease worldwide. Several interesting approaches have been developed, however their clinical impact has been low. One of the difficulties has been to find the proper molecular tracers to specifically tag pathognomonic lesions in AD brain, including not only amyloid aggregates but also filaments of the modified microtubule-associated protein tau. In this review, we analyze the evidence towards developing pathology-specific diagnostic tools for AD. We analyze the current evidence and clinical implications of new imaging technologies for AD, and how tau hypothesis and the amyloid cascade hypothesis will impact on these scientific efforts in the near future.
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Tau oligomers as potential target for immunotherapy for Alzheimer disease and tauopathies
Lasagna-Reeves CA, Castillo-Carranza DL, Jackson GR, Kayed R
[Purchase Article] [PMID: 21605039 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00034]

The aggregation and accumulation of the microtubule-associated protein (Tau) is a pathological hallmark of Alzheimer’s disease (AD) and many neurodegenerative diseases. For a long time research has focused on neurofibrillary tangles (NFTs) and other large meta-stable inclusions composed of aggregated hyperphosphorylated tau protein. The correlation between these structures and disease progression produced conflicting results, moreover the mechanism of their formation remains poorly understood. Lately, the significance and toxicity of NFTs have been challenged and new aggregated tau entity has emerged as the true pathogenic species in tauopathies and a possible mediator of Aβ toxicity in AD; specifically, aggregates of a size intermediate between monomers and NFTs so-called tau oligomers. Tremendous efforts have been devoted toward the optimization of a safe vaccine for AD by targeting Aβ peptide; despite the disappointing results, these studies produced a wealth of useful knowledge, which should be considered in developing tau-based immunotherapy.  Herein, we discuss the evidence supporting the critical role of tau oligomers in AD, the potential and challenges for targeting them by immunotherapy as a novel approach for AD treatment.
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Novel drugs affecting tau behavior in the treatment of Alzheimer´s disease and tauopathies
Navarrete LP, Pérez P, Morales I, Maccioni RB
[Purchase Article] [PMID: 21605038 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00035]

The anomalous aggregation of proteins into pathological filaments is a common feature of a many human diseases, often related to aging. In this context, neurodegenerative pathologies such as Alzheimer’s disease (AD) account for a major part of these protein misfolding diseases. AD is characterized by pathological aggregation of two proteins, tau and Aβ-amyloid. The intracellular neurofibrillary tangles (NFTs) and neuropil threads consists of filaments of the modified microtubule-associated protein tau, while extracellular amyloid plaques consists of filaments of Aβ-peptide. It is noteworthy that tau oligomers with a prefilamentous structure appear to play a role at early stages of AD and tauopathies, but also in asymptomatic patients with Braak-stage I neuropathology, where clinical symptoms of AD and NFTs in frontal cortex are absent. This suggests that an increase in tau oligomers levels occurs before individuals manifest clinical symptoms of AD. NFTs are one of the hallmarks of Alzheimer disease and other tauphaties. These aggregates are thought to be toxic to neurons, either by causing some neurotoxic signalling defects or by obstructing the cell function. Factors contributing to accumulation of tau aggregates include the increased rate of protein misfolding, generation of amyloidogenic oligomers, underactivity of repair systems such as chaperones and ubiquitin-proteasome system, or a failure of energy supply and antioxidant defense mechanisms.

There is not clear if the aggregated tau or oligomers cause cellular damage, but on the basis of the emergent need to have an early and effective treatment, lowering the production or removal of these aggregates appears as a pathway toward alleviating the disease. In the context of some of most relevant reports, we analyze why tau protein seems to be an interesting target for AD treatment, and the importance to understand the pathways of tau. aggregation. This knowledge will allow us to identify and optimize potential inhibitors that interact with aggregated forms of tau and hyperphosphorylated tau before the formation of the NFTs, offering a possible therapeutic route for AD treatment.
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A clinical perspective: anti tau’s treatment in  Alzheimer´s Disease
Fuentes P, Catalan J
[Purchase Article] [PMID: 21605037 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00036]

Alzheimer´s Disease (AD) physiopathology is not yet totally established. Nevertheless it is known that a  metabolism dysfunction of the amyloid beta precursor protein (APP) and the abnormal tau protein phosphorylation lead to the formation of neuritic plaques and neurofibrillary tangles, respectively. These events finally drive to the clinical expression of dementia.

Formally approved during the past decade, treatments for AD are lacking of an updating, being essentially symptomatic. Anticholinesterase agents have failed in providing a substantial improvement in the mental health condition of AD patients. On the other hand, antiamyloid strategies, have failed in their efficacy or security on their last development phases. In this context, tau represents a potential therapeutic target, by the action of drugs that diminish its aggegation, or acting by altering its phosphorylation or filaments formation. There is also anti-tau miscellaneous strategies such as normal microtubule-stabilizing agents. Thus, it might be possible that in a near future the neurodegenerative process could be stopped.
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The Role of the Anti-Amyloidogenic Secretase ADAM10 in Shedding the APP-like Proteins
Endres K, Fahrenholz F
[FULL-TEXT INQUIRY] [PMID: 21605036 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00037]

ADAM10 (A disintegrin and metalloproteinase 10) has been demonstrated as an enzyme with protective properties in Alzheimer’s disease: in mouse models it not only lowered generation of toxic A-beta peptides and formation of senile plaques but also alleviated learning deficits and enhanced synaptic density. This is due to cleavage of the amyloid precursor protein (APP) within its A-beta stretch and to the release of the extracellular domain of APP with neuroprotective function. Aside from cleaving APP, ADAM10 has been linked to over 40 putative substrates at least in cell culture. These substrates are connected with important cellular functions such as cell migration, stress response and transport. For this contribution we focussed on ADAM10 acting on the APP-like proteins since for some of their representatives - in particular APLP2 and APP-L - a shedding by ADAM10 has been demonstrated in vivo. In addition, the importance of these proteins, especially of APLP2, has been repeatedly shown by intense analysis of double and triple transgenic mice which lack APP in combination with one or both APLPs: several phenotypes such as defects in migration of neuroblasts, in formation of synapses and synaptic transmission have been reported. However, the specific contribution of either the uncleaved full-length proteins or their extracellular domains secreted upon ADAM10 activity has not been elucidated. In this review, we report on recent findings concerning shedding of APP-like proteins and resulting functional consequences.
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AICD nuclear signaling and its possible contribution to Alzheimer’s disease
Konietzko U
[Purchase Article] [PMID: 21605035 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00038]

Altered proteolytic processing of the β-amyloid precursor protein (APP) is a central event in familial and sporadic Alzheimer’s disease (AD). In a process termed regulated intramembrane proteolysis (RIP), APP first undergoes ectodomain shedding executed either by α- secretases at the plasma membrane or by β-secretase in the endosomal compartment. The remaining membrane-anchored stubs are cleaved within the membrane plane by the γ-secretase complex, releasing the APP intracellular domain (AICD) into the cytosol and leading to the generation of the Aβ peptide in the amyloidogenic pathway that is initiated by β-secretase. The Aβ peptides aggregate to form soluble oligomers and finally deposit into amyloid plaques that are a hallmark of AD. Recent evidence indicates a role for Aβ oligomers in regulating synaptic plasticity with excess amounts of oligomers disrupting synaptic function. The amyloid cascade hypothesis of AD is centered on the Aβ peptide, the APP fragment that has been most intensely studied, while other cleavage products have been largely neglected. The secreted ectodomain generated after α-cleavage in the non-amyloidogenic pathway has neurotrophic and neuroproliferative activities, thus opposing the neurotoxicity observed with high concentrations of Aβ. Further, in analogy to many other membrane proteins that are subject to RIP, AICD can translocate to the nucleus to regulate transcription. Many RIP substrates are localized to the synapse and thus could convey a direct signal from the synapse to the nucleus upon cleavage. Evidence indicates that only the amyloidogenic pathway generates AICD capable of nuclear signaling, due to the subcellular compartmentalization of APP processing. In aging and sporadic AD there is an increase in β-secretase levels and activity generating more Aβ peptides and concomitantly leading to an increase in AICD nuclear signaling. In this review, I summarize the current knowledge on AICD nuclear signaling and propose mechanisms to explain how this physiological function of APP might impact the pathology seen in AD.
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BACE1 dependent Neuregulin proteolysis
Fleck D, Garratt AN, Haass C, Willem M
[FULL-TEXT INQUIRY] [PMID: 21605034 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00039]

Neuregulin-1 (NRG1), which is also called acetylcholine receptor inducing activity (ARIA) or glial growth factor (GGF), signals as a ligand of ErbB receptors in a variety of important developmental processes but also later in life. NRG1 mediated signaling is crucial for cardiogenesis and the development of the breast. In the nervous system, NRG1 functions are essential for peripheral myelination, the establishment and maintenance of neuromuscular and sensorimotoric systems as well as for the plasticity of cortical neuronal circuits. There is strong evidence that deregulation of NRG1 is involved in breast cancer and schizophrenia. Many splice variants of NRG1 are expressed in the brain and all contain an EGF-like domain, which exerts the NRG1 function by limited proteolysis from its membrane bound precursor protein. In addition, most NRG1 isoforms contain a transmembrane domain, which is processed by γ-secretase after shedding. β-Secretase (β-site amyloid precursor protein cleaving enzyme 1; BACE1) has been identified based on its role as the rate limiting enzyme of amyloid-β-peptide (Aβ) production. Aβ is the major component of amyloid plaques in Alzheimer`s disease (AD). More recently it was shown that Neuregulin-1 activity is highly dependent on the cleavage by BACE1 during early postnatal development. In BACE1 KO mice a role for BACE1 dependent proteolysis of NRG1 in the process of peripheral myelination could be demonstrated. Here we summarize the current knowledge about the role of NRG1 proteolysis for ErbB receptor mediated signaling during development and in Alzheimer`s disease.
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Alpha-Secretase Cleavage of the Amyloid Precursor Protein: Proteolysis Regulated by Signaling Pathways and Protein Trafficking
Lichtenthaler SF
[FULL-TEXT INQUIRY] [PMID: 21605033 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00040]

α-secretase is the name for a metalloprotease activity, which is assumed to play a key role in the prevention of the molecular mechanisms underlying Alzheimer’s disease (AD). Proteases similar to α- secretase are essential for a wide range of biological processes, such as cell adhesion and embryonic development. The molecular culprit in AD is the amyloid β  peptide (Aβ), which derives from the amyloid precursor protein (APP) through sequential cleavage by the two proteases β and γ-secretase. In contrast,  α-secretase, which is the metalloprotease ADAM10, cleaves APP within the Aβ  domain, thus preventing Aβ generation. Additionally, it produces a secreted APP ectodomain with neurotrophic and neuroprotective properties. An increase in α-secretase cleavage is considered a therapeutic approach for AD, but the molecular mechanisms regulating α-secretase cleavage are only partly known. Protein kinase C and mitogen-activated protein kinase constitute central signaling hubs for the regulation of α-secretase cleavage. Additionally, recent studies increasingly demonstrate that the correct spatial and temporal localization of the two membrane proteins APP and α-secretase is essential for efficient α-secretase cleavage of APP. This review highlights the role of signaling pathways and protein trafficking in the control of APP α-secretase cleavage.
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An Overview of Notch Signaling in Adult Tissue Renewal and Maintenance
Sato C, Zhao G, Ilagan MXG
[FULL-TEXT INQUIRY] [PMID: 21605032 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00041]

The Notch pathway is a critical mediator of short-range cell-cell communication that is reiteratively used to regulate a diverse array of cellular processes during embryonic development and the renewal and maintenance of adult tissues. Most Notch-dependent processes utilize a core signaling mechanism that is dependent on regulated intramembrane proteolysis: Upon ligand binding, Notch receptors undergo ectodomain shedding by ADAM metalloproteases, followed by γ-secretase-mediated intramembrane proteolysis. This releases the Notch intracellular domain, which translocates to the nucleus to activate transcription. In this review, we highlight the roles of Notch signaling particularly in self-renewing tissues in adults and several human diseases and raise some key considerations when targeting ADAMs and γ-secretase as disease-modifying strategies for Alzheimer’s Disease.
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BDNF serum concentrations show no relationship with diagnostic group or medication status in neurodegenerative disease
Woolley JD, Strobl EV, Shelly WB, Miller BL, Mellon SH, Rankin KP
[FULL-TEXT INQUIRY] [PMID: 21605064 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00042]

Brain-derived neurotrophic factor (BDNF) is a growth factor implicated in neuronal survival. Studies have reported altered BDNF serum concentrations in patients with Alzheimer's disease. However, these studies have been inconsistent. Few studies have investigated BDNF concentrations across multiple neurodegenerative diseases, and no studies have investigated BDNF concentrations in patients with frontotemporal dementia. To examine BDNF concentrations in different neurodegenerative diseases, we measured serum concentrations of BDNF using enzyme-linked immunoassay in subjects with behavioral-variant frontotemporal dementia (bvFTD, n=20), semantic dementia (SemD, n=16), AD (n=34), and mild cognitive impairment (MCI, n=30), as well as healthy older subjects (HS, n=38). BDNF serum concentrations were compared across diagnoses and correlated with patterns of brain atrophy using voxel-based morphometry. No significant results were found in these analyses despite adequate power. These findings suggest that BDNF serum concentration is not a reliable biomarker to assess diagnosis in neurodegenerative disease
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Genetic polymorphisms in sigma-1 receptor and apolipoprotein E interact to influence the severity of Alzheimer's disease
Huang Y, Zheng L, Halliday G, Dobson-Stone C, Wang Y, Tang HD, Cao L, Deng YL, Wang G, Zhang YM, Wang JH, Hallupp M, Kwok J, Chen SD
[FULL-TEXT INQUIRY] [PMID: 21605063 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00043]

Apolipoprotein E (APOE) ε4 allele and sigma-1 receptor (SIGMAR1) c.5C (Q2P) polymorphisms have been acknowledged as risk factors for developing Alzheimer's disease (AD). However, whether these polymorphisms influence the disease process is unclear. Therefore, two cohorts with a clinical diagnosis of AD were recruited, a postmortem confirmed Australian cohort (82 cases) from the Australian Brain Bank Network, and a Chinese cohort with detailed clinical assessments recruited through an epidemiology study in Shanghai and through the neurology department outpatients clinic of Shanghai Ruijin Hospital (330 cases). SIGMAR1 Q2P and APOE genotyping was performed on all cases. Dementia severity in the Chinese cohort was assessed using MMSE scores, and the stages of senile plaques and neurofibrillary tangles (NFT) assessed in the Australian cohort. Associations between SIGMAR1 Q2P and APOE genotypes and disease severity were assessed using SPSS. Results confirmed that APOE ε4 allele associated with increased NFT stages and cognitive decline, with carriers with one APOE ε2 or ε3 allele often having better clinical outcomes compared to carriers with none or two ε2 or ε3 alleles respectively. SIGMAR1 c.5C polymorphism alone did not associate with MMSE score variability in Chinese or with pathological stages in Caucasians. However, the association studies revealed a significant genetic interaction between the APOE ε4 allele and SIGMAR1 2P carriers in both populations, i.e., in APOE non ε4 allele carriers, SIGMAR1 2P variant had increased cognitive dysfunction and more advanced stages of NFT. Our data demonstrate that SIGMAR1 and APOE interact to influence AD severity across ethnic populations
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The role for oxidative stress in aberrant DNA methylation in Alzheimer's Disease
Fleming JL, Phiel CJ, Toland AE
[Purchase Article] [PMID: 21605062 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00044]

Alzheimer's disease (AD) is a common, progressive neurodegenerative disorder without highly effective therapies. The etiology of AD is heterogeneous with amyloid-beta plaques, neurofibrillary tangles, oxidative stress, and aberrant DNA methylation all implicated in the disease pathogenesis. DNA methylation is a well-established process for regulating gene expression and has been found to regulate a growing number of important genes involved in AD development and progression. Additionally, aberrations in one-carbon metabolism are a common finding in AD patients with individuals exhibiting low S-adenosylmethionine and high homocysteine levels as well as low folate and vitamin B. Oxidative stress is considered one of the earliest events in AD pathogenesis and is thought to contribute largely to neuronal cell death. Emerging evidence suggests an interaction exists between oxidative stress and DNA methylation; however, the mechanism(s) remain unclear. This review summarizes known and potential genes implicated in AD that are regulated by DNA methylation and oxidative stress. We also highlight the evidence for the role of oxidative damage contributing to DNA hypomethylation in AD patients through several mechanisms as well as implications for disease understanding and therapeutic development.
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The Ability of Tolfenamic Acid to Penetrate the Brain: A Model for Testing the Brain Disposition of Candidate Alzheimer's Drugs Using Multiple Platforms
Subaiea GM, Alansi BH, Serra DA, Alwan M, and Zawia NH
[FULL-TEXT INQUIRY] [PMID: 21605061 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00045]

Evidence from our laboratory suggests that tolfenamic acid has a potential for slowing the progression of Alzheimer's disease (AD) through lowering cortical levels of the β-amyloid precursor protein (APP) and its pathogenic amyloid beta (Aβ) intermediates [1]. In this study, we examined the ability of tolfenamic acid to cross the blood brain barrier (BBB) by predicting its logBB and logPS values, the indexes of BBB permeability, using computational models. We also determined, via in vitro methods, the brain penetration capacity factor [(KIAM/MW4)x1010] using phosphatidylcholine column chromatography. The obtained logBB, logPS and (KIAM/MW4)x1010 values predicted that tolfenamic acid can passively transfer into the central nervous system (CNS). These results were validated in vivo using LC-MS analysis after administration of tolfenamic acid intravenously to guinea pigs and mice. The present study provides the first evidence of the ability of tolfenamic acid to cross the BBB and offers a comparative analysis of approaches used to predict the ability of compounds to penetrate into the brain.
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α‐Secretase in Alzheimer’s Disease and Beyond: Mechanistic, Regulation and Function in the Shedding of Membrane Proteins
Vincent B, Checler F
[FULL-TEXT INQUIRY] [PMID: 21605031 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00046]

Proteases regulate numerous physiological functions in all living organisms. Because, of their contribution to βAPP processing, α‐, β‐ and γ‐secretases have focused particular attention of researchers in the field of Alzheimer’s disease (AD) during the past 20 years. Whereas the β‐secretase BACE1 and the heterotetrameric presenilin‐dependent γ‐secretase complex were identified between 1995 and 2002, α‐secretase activity was attributed to previously described ADAM10 and ADAM17, two members of the type I integral membrane protein family called ADAMs (A Disintegrin And Metalloprotease). ADAM10 and/or ADAM17 target numerous substrates through various modes of action. This review focuses on the complex physiology of these α‐secretases and will document their contribution to cancers, diabetes, rheumatoid arthritis, and prion diseases besides their well characterized role in Alzheimer’s disease.
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γ-Secretase, apolipoprotein E and cellular cholesterol metabolism
Walter J
[FULL-TEXT INQUIRY] [PMID: 21605030 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00047]

Genetic studies demonstrate that the ε4 allele of the apolipoprotein (apo) E is a risk factor for late onset Alzheimer’s disease (AD). Apo E is the major component of lipoprotein particles in the brain that mediate transport of cholesterol and other lipids between neurons and glial cells, indicating an implication of cerebral lipid metabolism in the pathogenesis of AD. In addition, apo E is also involved in the metabolism and aggregation of the amyloid β-peptide (Aβ) that derives from proteolytic processing of the amyloid precursor protein (APP) and is found in plaques of AD brains. The generation of Aβ involves sequential cleavages of APP by proteases called β- and γ-secretase.

γ-Secretase is a high molecular weight protein complex containing presenilins as catalytically active subunits. Importantly, mutations in the genes of APP and the two homologous PS proteins are a major cause of familial early onset AD, indicating that the metabolism of APP and generation of Aβ play critical roles in the initiation of the disease.

This review focuses on the functional relation of γ-secretase complexes and the metabolism of lipoproteins in the brain. It is hypothesized that γ-secretase activity is critically involved in cellular lipid homeostasis and that impaired lipid metabolism contributes to the pathogenesis of AD.
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Role of APP and Aβ in Synaptic Physiology
Wang Z, Yang L, Zheng H
[FULL-TEXT INQUIRY] [PMID: 21605029 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00048]

Alzheimer’s disease (AD) is the most common cause of dementia in aging populations. Although amyloid plaques are the hallmark of AD, loss of synapses and synaptic dysfunction are closely associated with the duration and severity of cognitive impairment in AD patients. Amyloid precursor protein (APP) and its cleavage products including Aβ have been suggested as homeostatic regulators of synaptic activity. APP manipulation and Aβ application, in vitro and in vivo, affect synapse formation and synaptic transmission. Moreover, synaptic dysfunction and learning deficits precede Aβ plaque deposition, suggesting that synaptic alterations may underlie the initial development of the disease. Because of the pivotal role of APP and Aβ in AD pathogenesis, it is essential to understand how APP and Aβ modulate synaptic function. Here, we review the roles that APP and Aβ play at the synapses, with particular focus on recent findings for the importance of APP in synaptogenesis and synaptic function.
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Dietary omega 3 polyunsaturated fatty acids and Alzheimer’s disease: Interaction with apolipoprotein E genotype
Barberger-Gateau  P, Samieri C, Féart C, Plourde  M
[Purchase Article] [PMID: 21605054 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00049]

Epidemiological studies suggest a protective role of omega-3 poly-unsaturated fatty acids (n-3 PUFA) against Alzheimer’s disease (AD). However, most intervention studies of supplementation with n-3 PUFA have yielded disappointing results. One reason for such discordant results may result from inadequate targeting of individuals who might benefit from the supplementation, in particular because of their genetic susceptibility to AD. The ε4 allele of the apolipoprotein E gene (ApoE) is a genetic risk factor for late-onset AD. ApoE plays a key role in the transport of cholesterol and other lipids involved in brain composition and functioning. The action of n-3 PUFA on the aging brain might therefore differ according to ApoE polymorphism. The aim of this review is to examine the interaction between dietary fatty acids and ApoE genotype on the risk for AD.

Carriers of the ε4 allele tend to be the most responsive to changes in dietary fat and cholesterol. Conversely, several epidemiological studies suggest a protective effect of long-chain n-3 PUFA on cognitive decline only in those who do not carry the ε4 but with inconsistent results. An intervention study showed that only non-carriers had increased concentrations of long-chain n-3 PUFA in response to supplementation. The mechanisms underlying this gene-by-diet interaction on AD risk may involve impaired fatty acids and cholesterol transport, altered metabolism of n-3 PUFA, glucose or ketones, or modification of other risk factors of AD in ε4 carriers. Further research is needed to explain the differential effect of n-3 PUFA on AD according to ApoE genotype.
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Possible involvement of programmed cell death pathways in the neuroprotective action of polyphenols
Bastianetto S, Krantic S, Chabot J-G, Quirion R
[FULL-TEXT INQUIRY] [PMID: 21605053 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00050]

One of the hallmarks of Alzheimer’s disease is the accumulation of senile plaques composed of extra-cellular aggregates of beta-amyloid (Aβ) peptides. It is well established that at least in vitro, Aβtriggers apoptotic cell death via the activation of caspase-dependent and -independent cell death effectors, namely caspase-3 and apoptosis inducing factor (AIF), respectively. Epidemiological studies have reported that elderly people have a lower risk (up to 50%) of developing dementia if they regularly eat fruits and vegetables and drink tea and red wine (in moderation). Numerous studies indicate that polyphenols derived from these foods and beverages account for the observed neuroprotective effects. In particular, we have reported that polyphenols extracted from green tea (i.e. epigallocatechin gallate or EGCG) and red wine (i.e. resveratrol) block Aβ-induced hippocampal cell death, by at least partially inhibiting Aβfibrillisation. It has been shown that polyphenols may also modulate caspase-dependent and -independent programmed cell death (PCD) pathways. Indeed, polyphenols including resveratrol, EGCG and luteolin significantly inhibit the activation of the key apoptotic executioner, caspase-3 and are able to modulate mitogen-activated protein kinases known to play an important role in neuronal apoptosis. Moreover, it has been reported that polyphenols may exert their anti-apoptotic action by inhibiting AIF release from mitochondria, thus providing new mechanism of action for polyphenols. This review aims to update the current knowledge regarding the differential effects of polyphenols on PCD pathways and discuss their putative neuroprotective action resulting from their capacity to modulate these pathways.
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Nutritional Approaches to Modulate Oxidative Stress in Alzheimer’s Disease
Pocernich CB, Bader Lange ML, Sultana R, Butterfield DA
[FULL-TEXT INQUIRY] [PMID: 21605052 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00051]

Alzheimer’s disease (AD) brain is characterized by amyloid β–peptide (Aβ) deposits, neurofibrillary tangles, synapse loss, and extensive oxidative stress.  Aβ-induced oxidative stress is indexed by protein oxidation, lipid peroxidation, free radical formation, DNA oxidation and neuronal cell death.  Oxidative stress is combated by antioxidants.  Antioxidants and nutrition have long been considered as an approach to slow down AD progression.  In this review, we focus on antioxidants that have been shown to protect against Aβ-induced oxidative stress, particularly vitamin E, ferulic acid, various polyphenols, including quercetin and resveratrol, α-lipoic acid, N-acetyl-L-cysteine (NAC), curcumin, epigallocatechin gallate (EGCG), and γ-glutamylcysteine ethyl ester (GCEE). Brain-accessible antioxidants with both radical scavenging properties and ability to induce protective genes are hypothesized to be helpful in treatment for AD.
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Omega-3 polyunsaturated fatty acids in Alzheimer’s disease: key questions and partial answers
Calon F
[FULL-TEXT INQUIRY] [PMID: 21605051 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00052]

The current rise in the prevalence of Alzheimer’s disease (AD) is unfortunately not matched by new treatment options. In the last 10 years, epidemiological, preclinical and clinical data have enlightened the possible preventive action of omega-3 polyunsaturated fatty acids (n-3 PUFA) in AD and other diseases. While the contribution of recent studies to our general knowledge is priceless, many important new questions have been raised. In the present review, we aim at addressing some of these timely interrogations. First, the transport of n-3 PUFA across the blood-brain barrier is underscored based on preclinical data. Second, the relative contribution of two neuroactive n-3 PUFA found in fish oil, docosahexaenoic acid (DHA; 22:6 n-3) and eicosapentaenoic acid (EPA, 20:5 n-3), remains unclear and is reviewed. Third, clinical trials on neurodegenerative diseases consistently remind us that treating early is critical, and this is likely to be the case with n-3 PUFA in AD as well. Fourth, we draw attention to the possibility that the current knowledge translation approach to make health recommendations might have to be adapted to non-patentable endogenous compounds like n-3 PUFA. We propose that answers to these critical questions will be instrumental toward a rational use of n-3 PUFA in AD.
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Metabolic Syndrome, Mild Cognitive Impairment, and Dementia
Panza F, Frisardi V, Seripa D, Imbimbo BP, Sancarlo D, D’Onofrio G, Addante F, Paris F, Pilotto A, Solfrizzi V
[FULL-TEXT INQUIRY] [PMID: 21605050 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00053]

At present, the search for preventive strategies for cognitive decline and dementia appears to be of crucial importance, given that the therapeutic options currently available have demonstrated limited efficacy. Cumulative epidemiological evidence suggested that vascular and vascular-related factors may be important for the development of age-related cognitive decline (ARCD), mild cognitive impairment (MCI), and cognitive decline of degenerative (Alzheimer’s disease, AD) or vascular origin (vascular dementia, VaD). Among vascular-related factors, metabolic syndrome (MetS) has been associated with the reduced risk of predementia syndromes (ARCD and MCI), overall dementia, and VaD, but contrasting findings also exist on the possible role of MetS in AD. In the next future, trials could then be undertaken to determine if modifications of these risks including inflammation, another factor probably related to MetS, could lower risk of developing cognitive decline. If MetS is associated with increased risk of developing cognitive impairment, then early identification and treatment of these individuals at risk might offer new avenues for disease course modification. Future research aimed at identifying mechanisms that underlie comorbid associations will not only provide important insights into the causes and interdependencies of predementia and dementia syndromes, but will also inspire novel strategies for treating and preventing these disorders. At present, vascular risk factor management could be decisive in delaying the onset of dementia syndromes or in preventing the progression of predementia syndromes.
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Tyrosol and hydroxytyrosol, two main components of olive oil, protect N2a cells against amyloid-β-induced toxicity. Involvement of the NF-κB signaling
St-Laurent-Thibault C, Arseneault M, Longpré F, Ramassamy C
[FULL-TEXT INQUIRY] [PMID: 21605049 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00054]

Alzheimer’s disease (AD) is the most common form of dementia. Recently, a number of epidemiological studies have evidence that some dietary factors such as low antioxidants and vitamins intake could increase the risk of AD. In the opposite, diets rich in unsaturated fatty acids, in polyphenols, vitamins and antioxidants were identified as preventive factors. Several studies have reported that adherence to the Mediterranean diet (MeDi) was associated with a reduction in incident of dementia. The beneficial effect of MeDi may be the result of the association of some individual and non-identified food components and high consumption of olive oil.

In this study we have investigated the protective effects of two components of olive oil, tyrosol (Tyr) and hydroxytyrosol (OH-Tyr), against Aβ-induced toxicity. In cultured neuroblastoma N2a cells, we found that Aβ_25-35 (100mg/ml) treatment induced a decrease of glutathione (GSH) and the activation of the transcription factor NF-κB and cell death. Our results demonstrated that the number of cell death decreased when cells were co-treated with Aβ and Tyr or OH-Tyr. However, neither of these phenolic compounds was able to prevent the decrease of GSH induced by H₂O₂ or Aβ. We found that the increase in the nuclear translocation of the NF-kB subunits after Aβ exposure was attenuated in the presence of Tyr or OH-Tyr. These results identified two individual food components of the MeDi as neuroprotective agent against Aβ and their potential involvement in the beneficial effect of the MeDi for the prevention of AD.
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Dietary patterns in Alzheimer’s disease and cognitive aging
Gu Y, Scarmeas N
[FULL-TEXT INQUIRY] [PMID: 21605048 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00055]

Much of the attention on diet and Alzheimer’s disease (AD) or cognition among the elderly has focused on the role of single nutrients or foods, while available information on dietary pattern (DP) analysis, which better reflects the complexity of the diet, is sparse. In this review, we describe different patterning approaches and present studies performed to date that have assessed the associations between DPs and risk of AD or cognitive function in the elderly. Three patterning approaches have been most commonly used: (i) hypothesis-based that use dietary quality indexes or scores (e.g. Mediterranean pattern), (ii) data-driven that use factor or cluster analysis to derive DPs, (iii) reduced rank regression which combines characteristics of the former two approaches. Despite differences existing among the approaches, DPs characterized by higher intake of fruits, vegetables, fish, nuts and legumes, and lower intake of meats, high fat dairy, and sweets seemed to be associated with lower odds of cognitive deficits or reduced risk of AD. Overall, the inherent advantages as well as the existing evidence of DP analyses strongly suggest that this approach may be valuable in AD and aging research.  Further studies are warranted, though, to confirm the findings in different population settings, to address some methodological issues, and possibly utilize the information for future clinical trial design.
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Mediterranean Diet in Predementia and Dementia Syndromes
Solfrizzi V, Frisardi V, Seripa D, Logroscino G, Imbimbo BP, D’Onofrio G, Addante F, Sancarlo D, Cascavilla L, Pilotto A, Panza F
[FULL-TEXT INQUIRY] [PMID: 21605047 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00056]

There is a critical need to potentially individualize new strategies able to prevent and to slow down the progression of predementia and dementia syndromes. Only recently higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline although the Mediterranean diet (MeDi) combines several foods, micro- and macronutrients already separately proposed as potential protective factors against dementia and predementia syndromes. In fact, elevated saturated fatty acids could have negative effects on age-related cognitive decline and mild cognitive impairment (MCI). Furthermore, at present, epidemiological evidence suggested a possible association among fish consumption, monounsaturated fatty acids and polyunsaturated fatty acids (PUFA) (particularly, n-3 PUFA) and reduced risk of cognitive decline and dementia. Light to moderate alcohol use may be associated with a reduced risk of incident dementia and Alzheimer’s disease (AD), while for vascular dementia, cognitive decline, and predementia syndromes the current evidence is only suggestive of a protective effect. Finally, the limited epidemiological evidence available on fruit and vegetable consumption and cognition generally supported a protective role of these macronutrients against cognitive decline, dementia, and AD. Moreover, recent prospective studies provided evidence that higher adherence to a Mediterranean-type diet could be associated with slower cognitive decline, reduced risk of progression from MCI to AD, reduced risk of AD, and decreased all-causes mortality in AD patients. These findings suggested that adherence to the MeDi may affect not only the risk for AD, but also for predementia syndromes and their progression to overt dementia. Nonetheless, at present, no definitive dietary recommendations are possible. However, high levels of consumption of fats from fish, vegetable oils, non-starchy vegetables, low glycemic fruits, and diet low in foods with added sugars and with moderate wine intake should be encouraged. In fact, this dietary advice is in accordance with recommendations for lowering the risk of cardiovascular disease, obesity, diabetes, and hypertension and might open new ways for the prevention and management of cognitive decline and dementia.
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Association and Causal Relationship of Midlife Obesity and Related Metabolic Disorders with Old Age Cognition
Laitala VS, Kaprio J, Koskenvuo M, Räihä I,  Rinne JO and  Silventoinen K
[FULL-TEXT INQUIRY] [PMID: 21619517 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00057]

Objective: Epidemiological studies suggest a relationship between midlife metabolism and old age cognition. We examined the effect of midlife BMI and related metabolic conditions on old age cognitive performance and whether there was evidence from direct causal pathways behind these associations in a large sample of Finnish twins. Design: Midlife variables of 2606 twin individuals were based on postal questionnaires and registry records. Old age cognitive status was measured by using a validated telephone interview. Results: Midlife BMI, cardiovascular disease, hypertension and diabetes were each associated with old age cognition when adjusted for sex, education, birth year and age at the interview.

Similarly, overweight increased the risk for categories of mild impairment of cognitive function and likely dementia. Cardiovascular disease diminished the mean cognitive score also among discordant twin pairs (β -estimate=1.10, pvalue= 0.012). Weight gain more than 1.7 kg/m2 and loss more than 2 kg/m2 within an average of 5.6 years were associated with lower cognitive performance independently of BMI. An additive genetic correlation explained the association between BMI and old age cognition (rA=-0.12, 95% CI -0.21; -0.03), but adjustment for education led to loss of significance (rA=-0.06, 95% CI -0.16; 0.03). Conclusions: Midlife metabolic diseases, especially diabetes, are independently associated with impaired cognition in old age. Even a more subtle weight change than suggested previously was associated with lower old age cognition. There was evidence from direct causal pathway between cardiovascular disease and old age cognition, while the correlation between midlife BMI and old age cognition was explained mostly by genetic factors. Abstract: Objective: Epidemiological studies suggest a relationship between midlife metabolism and old age cognition. We examined the effect of midlife BMI and related metabolic conditions on old age cognitive performance and whether there was evidence from direct causal pathways behind these associations in a large sample of Finnish twins. Design: Midlife variables of 2606 twin individuals were based on postal questionnaires and registry records. Old age cognitive status was measured by using a validated telephone interview. Results: Midlife BMI, cardiovascular disease, hypertension and diabetes were each associated with old age cognition when adjusted for sex, education, birth year and age at the interview. Similarly, overweight increased the risk for categories of mild impairment of cognitive function and likely dementia. Cardiovascular disease diminished the mean cognitive score also among discordant twin pairs (β -estimate=1.10, pvalue=0.012). Weight gain more than 1.7 kg/m2 and loss more than 2 kg/m2 within an average of 5.6 years were associated with lower cognitive performance independently of BMI. An additive genetic correlation explained the association between BMI and old age cognition (rA=-0.12, 95% CI -0.21; -0.03), but adjustment for education led to loss of significance (rA=-0.06, 95% CI -0.16; 0.03). Conclusions: Midlife metabolic diseases, especially diabetes, are independently associated with impaired cognition in old age. Even a more subtle weight change than suggested previously was associated with lower old age cognition. There was evidence from direct causal pathway between cardiovascular disease and old age cognition, while the correlation between midlife BMI and old age cognition was explained mostly by genetic factors.
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Tau as A Therapeutic Target for Alzheimer’s Disease
Boutajangout A, Sigurdsson EM, Krishnamurthy PK
[FULL-TEXT INQUIRY] [PMID: 21679154 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00058]

Neurofibrillary tangles (NFTs) are one of the pathological hallmarks of Alzheimer’s disease (AD) and are primarily composed of aggregates of hyperphosphorylated forms of the microtubule associated protein tau. It is likely that an imbalance of kinase and phosphatase activities leads to the abnormal phosphorylation of tau and subsequent aggregation. The wide ranging therapeutic approaches that are being developed include to inhibit tau kinases, to enhance phosphatase activity, to promote microtubule stability, and to reduce tau aggregate formation and/or enhance their clearance with small molecule drugs or by immunotherapeutic means. Most of these promising approaches are still in preclinical development whilst some have progressed to Phase II clinical trials. By pursuing these lines of study, a viable therapy for AD and related tauopathies may be obtained.
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Effects of Galantamine in Alzheimer’s Disease: Double-blind Withdrawal Studies Evaluating Sustained Versus Interrupted Treatment
Gaudig M, Richarz U, Han J, Baelen BV, Schäuble B
[Purchase Article] [PMID: 21707533 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00059]

To evaluate the effects of galantamine withdrawal, and compare this with uninterrupted therapy, two 6-week double-blind withdrawal studies (Studies 1 and 2) were performed. These enrolled individuals who had completed one of two 3- or 5-month randomized clinical trials (parent trials) involving patients with mild to moderate Alzheimer’s disease (AD). In Study 1 (GAL-USA-11; n=723), patients continuously treated with galantamine 16 mg/day exhibited a mean (± standard error [SE]) improvement in 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale score of 1.8 (± 0.46) points at Week 6 compared with the parent trial baseline, (p<0.001 vs placebo; observed cases analysis). Over the same period, patients switched from galantamine to placebo and those who had received continuous placebo, exhibited mean (± SE) deteriorations of 0.7 (± 0.49) and 1.2 (± 0.49) points, respectively. Similar trends were apparent in Study 2 (GAL-USA-5; n=118). In Study 1, subgroup analyses demonstrated cognitive benefits with continuing galantamine treatment and deterioration associated with galantamine withdrawal in patients with advanced moderate AD (baseline Mini-Mental State Examination score ≤14) and in individuals deemed non-responsive in terms of Clinician’s Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus) evaluation at the end of the parent trial (CIBIC-plus score >4). No safety issues were identified. In patients with mild to moderate AD who have exhibited cognitive benefits from up to 5 months’ galantamine treatment, continuing therapy reinforces previously achieved benefit, whereas in patients in whom galantamine is discontinued, although no safety concerns arise, the natural progression of AD is apparent.
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Editorial: Tau protein and Alzheimer´s disease
Maccioni RB
[BSP/CAR/E-Pub/00060]

This Special issue of Current Alzheimer´s Research contains papers representing the very broad research efforts devoted to tau protein in Alzheimer´s disease (AD) and other tauopathies, and commemorates 35 years after tau’s discovery. I thank Dr. Debomoy Lahiri for the honor to handle this issue, and express my gratefulness of the many creative scientists that participated with perseverance and faith to produce a truly exciting issue. Researchers of AD have labored for longer than four decades to solve this complex disease. Although a large amount of knowledge in neurosciences has been generated the data has not provided effective solutions for this devastating disease.  AD is a progressive neurodegenerative disorder characterized by two major neuropathologic hallmarks: extracellular senile plaques composed of amyloid beta (Aβ) and intracellular neurofibrillary tangles (NFT) made of tau. Even though the causes of this disease are still unknown, many interesting hypotheses have been postulated. Considering AD as a result of multifactorial events, it is possible to think that a concatenated series of damage signals affects brain cells, mainly microglial cells, thus triggering an abnormal response in neuro-immunomodulation with consequent effects on neurons. A common molecular feature of these anomalous signals leads to tau self-aggregation into oligomers as a final event. Tau aggregates and filamentous structures generate paired helical filaments (PHFs) and NFTs at advanced stages of the disease. Thus, tau pathology appears to be the final result of a series of abnormal mechanisms occurring at the level of the affected neurons. Several genetic and environmental risk factors have been proposed including age, apolipoprotein E4 genotype, diabetes, cardiovascular disease, mutations in the amyloid protein precursor (APP), education attainment, elevated cholesterol, depression, head injury, mutations in the presenilin genes and others.

NFT’s were first described by Alois Alzheimer in 1906. In the early sixties, ultrastructural analysis showed that NFT’s were composed of paired helical filaments (PHF). In 1984, Iqbal and colleagues isolated PHF’s from pathologically confirmed AD brain. Thereafter, in 1985 it was discovered that the microtubule associated protein tau was a major component and antigenic determinant of PHF. This finding was quickly confirmed by several other groups including Kosik. Tau was discovered in the middle 70´s and baptized by Kirschner´s group as tau (Greek letter in contrast with tubulin since it exhibited similar electrophoretic migration). In the meantime several laboratories including ours had discovered a protein that promoted microtubule assembly, which turned out to be the same tau protein reported by Kirschner´s laboratory.  At the same time blotting of a supernatant preparation from AD brain with an antibody known as Alz 50showed a band with an apparent molecular weight of 68 kDa. The authors suggested that the Alz 50 antigen was unlikely to be tau, but it was later shown that Alz 50 did in fact recognize an epitope found in phosphorylated tau (note Alz50 is on phospho Tau but it is not a phospho epitope). The novel idea that PHF’s from AD brain were composed of phosphorylated variants of tau was first reported by Grundke-Iqbal et al. and Ihara and coworkers around 1986. This finding is of relevance since tau’s phosphosylation can affect its microtubule binding ability. In 1998 we postulated, along with the groups of Lee and Tsai, that deregulation of a critical protein kinase cdk5 was instrumental for the pathological phosphorylations of tau, and that blocking this enzyme prevented neuronal degeneration.  Several groups have also identified other kinases that play a role in PHF tau phosphorylation. More recently, Harish Pant provided insight into the alterations in the sensitive equilibrium between kinases and protein phosphatases in the process of pathological tau modifications.

Our current understanding of tau’s functional organization has been supported by the discovery of mutations in the tau gene which are responsible for a range of neurodegenerative disorders collectively termed tauopathies. They are also characterized by the presence of aggregated tau deposits. However, no mutations in the tau gene are associated with AD. With an increasing number of disorders proposed to be caused by tau pathology, there is a very urgent need to develop viable therapeutic avenues that addess tau abnormalities.

Currently there is no cure for  tau related diseases, however we hope that with the many thoughts on this disorder highlighted in this issue we can approach an effective treatment. Here, in this series of papers some of the extensive data that supports a causative role for tau protein in the pathogenesis of tauopathies is described. For targeting the deregulation of tau protein in an appropriate temporal and spatial manner, the various potential treatment options discussed are likely to have a therapeutic value. Further work on improving the specificity, efficacy and minimizing potential side effects of these treatments remains to be completed, but these are exciting times for the tau research community.
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Metric distances between hippocampal shapes indicate different rates of change over time in nondemented and demented subjects
Ceyhan E, Beg MF, Ceritoğlu C, Wang L, Morris JC, Csernansky JG, Miller MI and Ratnanather JT
[FULL-TEXT INQUIRY] [PMID: 21875412 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00061]

 In this article, we use longitudinal morphometry (shape and size) measures of hippocampus in subjects with mild dementia of Alzheimer type (DAT) and nondemented controls in logistic discrimination.  The morphometric measures we use are volume and metric distance measures at baseline and follow-up (two years apart from baseline).  Morphometric differences with respect to a template hippocampus were measured by the metric distance obtained from the large deformation diffeomorphic metric mapping (LDDMM) algorithm. LDDMM assigns metric distances on the space of anatomical images, thereby allowing for the direct comparison and quantization of morphometric changes.  We also apply principal component analysis (PCA) on volume and metric distance measures to obtain principal components that capture some salient aspect of morphometry. We construct classifiers based on logistic regression to distinguish diseased and healthy hippocampi (hence potentially diagnose the mild form of DAT).  We consider logistic classifiers based on volume and metric distance change over time (from baseline to follow-up), on the raw volumes and metric distances, and on principal components from various types of PCA analysis. We provide a detailed comparison of the performance of these classifiers and guidelines for their practical use. Moreover, combining the information conveyed by volume and metric distance measures by PCA can provide a better biomarker for detection of dementia compared to volume, metric distance, or both.
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Dogs with Cognitive Dysfunction Syndrome: A Natural Model of Alzheimer’s Disease
Bosch MN, Pugliese M, Gimeno-Bayón J, Rodríguez MJ and Mahy N
[FULL-TEXT INQUIRY] [PMID: 21875411 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00062]

In the search for appropriate models for Alzheimer’s disease (AD) involving animals other than rodents, several laboratories are working with animals that naturally develop cognitive dysfunction. Among the animals tested, dogs are quite unique in helping to elucidate the cascade of events that take place in brain amyloid-beta (Aβ), deposition aging, and cognitive deficit. Recent innovative research has validated human methods and tools for the analysis of canine neuropathology and has allowed the development of two different approaches to investigate dogs as natural models of AD. The first approach relates AD-like neuropathy with the decline in memory and learning ability in aged housed dogs in a highly controlled laboratory environment. The second approach involves research in family-owned animals with cognitive dysfunction syndrome. In this review, we compare the strengths and limitations of housed and family-owned canine models, and appraise their usefulness for deciphering the early mechanisms of AD and developing innovative therapies.
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Influence of Lithium Treatment on GDNF Serum and CSF Concentrations in Patients with Early Alzheimer´s Disease
Straten G, Saur R, Laske C, Gasser T, Annas P, Basun H and Leyhe T
[FULL-TEXT INQUIRY] [PMID: 21875410 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00063]

Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer´s disease (AD). One possible mechanism of action might be the induction of neurotrophins. Recently, we found a significant increase of brain-derived neurotrophic factor (BDNF) serum levels in AD patients treated with lithium and a significant decrease of ADAS Cog sum scores in comparison to placebo-treated patients. In another previous study we have shown that glial cell line-derived neurotrophic factor (GDNF) levels in CSF of patients with early AD are increased most probably due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease. Here we assessed the influence of a lithium treatment on GDNF serum and cerebrospinal fluid (CSF) concentrations in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. We found a significant negative correlation of lithium concentration in serum with GDNF concentration in CSF at the end of treatment (r = -0.585, p = 0.036) and with the difference of GDNF concentration in CSF before and after treatment (r = -0.755, p = 0.003). However, we could not show a difference in GDNF concentrations between the patients after the treatment with lithium or placebo (serum, mean ± standard deviation: 434.3 ± 117.9 pg/ml versus 543.8 ± 250.0 pg/ml, p = 0.178; CSF, 62.3 ± 37.4 pg/ml versus 72.8 ± 43.9 pg/ml, p = 0.511). The findings of the present investigation indicated that beneficial effects of the lithium treatment might reduce the necessity of enhanced GDNF expression in the CNS in early AD.
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Matrix Metalloproteinase-2 and Epidermal Growth Factor are Decreased in Platelets of Alzheimer Patients
Hochstrasser T, Ehrlich D, Marksteiner J, Sperner-Unterweger B and Humpel C
[FULL-TEXT INQUIRY] [PMID: 21875409 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00064]

Alzheimer’s disease (AD) is the most prevalent type of dementia. Despite considerable advances in diagnostic accuracy, diagnostic procedures that are easily accessible are still sorely needed. Blood biomarkers are therefore in the focus of research. Platelets contain a high concentration of the amyloid precursor protein (APP), which has been mentioned as a potentially useful diagnostic marker. The aim of the present study was to analyze various cell adhesion molecules (CAMs), cytokines, growth factors, and matrix metalloproteinases (MMPs) in platelets of AD and mild cognitively impaired (MCI) patients as compared to healthy controls. Our data show a significant decrease in the levels of epidermal growth factor (EGF) and of MMP-2 in platelets of AD patients and decreased levels of MMP-2 in MCI. The APP ratio was slightly but not significantly decreased in AD patients, whereas CD40L and serotonin were unchanged. Our findings demonstrate specific changes in AD platelets. Whether these biomarkers can be established as potential early diagnostic biomarkers for AD remains to be established in longitudinal studies.
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Optimized turmeric extract reduces β-Amyloid and phosphorylated Tau protein burden in Alzheimer’s transgenic mice
Douglas Shytle R, Tan J, Bickford PC, Rezai-zadeh K, Hou L, Zeng J, Sanberg PR, Sanberg CD, Alberte RS, Fink RC, and Roschek Jr. B
[FULL-TEXT INQUIRY] [PMID: 21875408 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00065]

In a previous in vitro study, the standardized turmeric extract, HSS-888, showed strong inhibition of Aβ aggregation and secretion in vitro, indicating that HSS-888 might be therapeutically important. Therefore, in the present study, HSS-888 was evaluated in vivo using transgenic ‘Alzheimer’ mice (Tg2576) over-expressing Aβ protein. Following a six-month prevention period where mice received extract HSS-888 (5mg/mouse/day), tetrahydrocurcumin (THC) or a control through ingestion of customized animal feed pellets (0.1% w/w treatment), HSS-888 significantly reduced brain levels of soluble (~40%) and insoluble (~20%) Aβ as well as phosphorylated Tau protein (~80%). In addition, primary cultures of microglia from these mice showed increased expression of the cytokines IL-4 and IL-2. In contrast, THC treatment only weakly reduced phosphorylated Tau protein and failed to significantly alter plaque burden and cytokine expression. The findings reveal that the optimized turmeric extract HSS-888 represents an important step in botanical based therapies for Alzheimer’s disease by inhibiting or improving plaque burden, Tau phosphorylation, and microglial inflammation leading to neuronal toxicity.
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N-Methyl D-Aspartate (NMDA) Receptor Antagonists and Memantine Treatment for Alzheimer’s Disease, Vascular Dementia and Parkinson’s Disease
Olivares D, Deshpande VK, Shi Y, Lahiri DK, Greig NH, Rogers JT and Huang X
[FULL-TEXT INQUIRY] [PMID: 21875407 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00066]

Memantine, a partial antagonist of N-methyl-D-aspartate receptor (NMDAR), approved for moderate to severe Alzheimer’s disease (AD) treatment within the US and Europe under brand name Namenda (Forest), Axura and Akatinol (Merz), and Ebixa and Abixa (Lundbeck), may have potential in alleviating additional neurological conditions, such as vascular dementia (VD) and Parkinson’s disease (PD). In various animal models, memantine has been reported to be a neuroprotective agent that positively impacts both neurodegenerative and vascular processes. While excessive levels of glutamate result in neurotoxicity, in part through the over-activation of NMDARs, memantine—as a partial NMDAR antagonist, blocks the NMDA glutamate receptors to normalize the glutamatergic system and ameliorate cognitive and memory deficits. The key to memantine’s therapeutic action lies in its uncompetitive binding to the NMDAR through which low affinity and rapid off-rate kinetics of memantine at the level of the NMDAR-channel preserves the physiological function of the receptor, underpinning memantine’s tolerability and low adverse event profile. As the biochemical pathways evoked by NMDAR antagonism also play a role in PD and since no other drug is sufficiently effective to substitute for the first-line treatment of L-dopa despite its side effects, memantine may be useful in PD treatment with possibly fewer side effects. In spite of the relative modest nature of its adverse effects, memantine has been shown to provide only a moderate decrease in clinical deterioration in AD and VD, and hence efforts are being undertaken in the design of new and more potent memantine-based drugs to hopefully provide greater efficacy.
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Stage-dependent agreement between cerebrospinal fluid proteins and FDG-PET findings in Alzheimer’s disease
Yakushev I, Müller MJ, Buchholz H-G, Lang U,  Rossmann H, Hampel H, Schreckenberger M and Fellgiebel  A
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00067]

Cerebral hypometabolism and abonrmal levels of amyloid beta (Aβ), total (t-tau) and phosphorylated tau (p-tau) proteins in cerebrospinal fluid (CSF) are established biomarkers of Alzheimer’s disease (AD). We examined the agreement between these biomarkers in a single center study of patients with AD of severity extending over a wide range.

Forty seven patients (MMSE 21.4±3.6, range 13-28 points) with incipient (n=11) and probable (n=36) AD underwent positron emission tomography with [18F]-fluorodeoxyglucose (FDG-PET) and lumbar puncture for CSF assays of Aβ_1-42, p-tau₁₈₁, and t-tau. All findings were classified as either positive or negative for AD. Statistical analyses were performed for the whole sample (n=47) and for the subgroups stratified as mild (MMSE >20 points, n=30) and moderate (MMSE <21 points, n=17) AD.

In the whole patient sample, the agreement with the FDG-PET finding was 77% (chance-corrected kappa [k]=0.34, p=0.016) for t-tau, 68% (k=0.10, n.s.) for p-tau181, and 68% (k=0.04, n.s.) for Aβ_1-42. No significant agreement was found in the mild AD subgroup, while there was a strong agreement for t-tau (94%, k=0.77, p=0.001) and p-tau₁₈₁ (88%, k=0.60, p=0.014) in the moderate AD group.

A significant agreement between the FDG-PET and CSF tau findings in patients with AD supports the view that both are markers of neurodegeneration. CSF tau proteins and FDG-PET might substitute each other as supportive diagnostic tools in patients with suspected moderate-to-severe Alzheimer’s dementia, while this is not the case in subjects at an earlier disease stage.
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Intrahippocampal Amyloid-β (1-40) Injections Injure Medial Septal Neurons in Rats
Colom LV,  Castaneda MT, Hernandez S, Perry G , Jaime S and Touhami A
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00068]

Alzheimer’s disease (AD) is a devastating disorder that leads to memory loss and dementia. Neurodegeneration of cholinergic neurons in the septum and other basal forebrain areas is evident in early stages of AD. Glutamatergic neurons are also affected early in AD. In these stages, amyloid-β-peptide (Aβ) plaques are present in the hippocampus and other cortices but not in the basal forebrain, which includes the septum. We postulate that early deposition of hippocampal Aβ damages the axon terminals of cholinergic and glutamatergic septo-hippocampal neurons, leading to their degeneration. To determine the mechanisms underlying septal degeneration, fibrillar Aβ1-40 was injected into the Cornu Ammonis (CA1) hippocampal region of rats. Controls were injected with reverse peptide Aβ40-1. A 16% reduction in NeuN+ cells was observed around the injection sites when compared to controls (p<0.05) one week after injections. Stereology was used to estimate the number of choline acetyl transferase (ChAT), glutamate and glutamic acid decarboxylase 67 (GAD67) immunoreactive septal neurons. Medial septal ChAT and glutamate immunoreactive neurons were reduced 38% and 26%, respectively by hippocampal injections of Aβ1-40 peptide in relation to controls. In contrast, the number of GAD67 inmunoreactive neurons was not significantly reduced. Apoptotic cells were detected in the medial septal region of Aβ1-40 treated animals but not in controls. These results indicate that limited Aβ-induced hippocampal lesions lead to an overall damage of vulnerable septal neuronal populations, most likely by Aβ interaction with septo-hippocampal axon terminals. Thus, axon terminals constitute an important target for novel therapeutics dedicated to control Aβ-induced toxicity.
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Altered calmodulin degradation and signaling in non-neuronal cells from Alzheimer’s disease patients
Esteras N, Muñoz U,  Alquézar C, Bartolomé F, Bermejo-Pareja F and Martín-Requero A
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00069]

Previous work indicated that changes in Ca²⁺/calmodulin (CaM) signaling pathway are involved in the control of proliferation and survival of immortalized lymphocytes from Alzheimer’s disease (AD) patients. We examined the regulation of cellular CaM levels in AD lymphoblasts. An elevated CaM content in AD cells was found when compared with control cells from age-matched individuals. We did not find significant differences in the expression of the three genes that encode CaM: CALM1, 2, 3, by real time RT-PCR.  However, we observed that the half-life of CaM was higher in lymphoblasts from AD than in control cells, suggesting that degradation of CaM is impaired in AD lymphoblasts. The rate of CaM degradation was found to be dependent on cellular Ca²⁺ and ROS levels. CaM degradation occurs mainly via the ubiquitin-proteasome system. Increased levels of CaM were associated with overactivation of PI3K/Akt and CaMKII. Our results suggest that increased levels of CaM synergize with serum to overactivate PI3K/Akt in AD cells by direct binding of CaM to the regulatory a-subunit (p85) of PI3K. The systemic failure of CaM degradation, and thus of Ca²⁺/CaM-dependent signaling pathways, may be important in the etiopathogenesis of AD.
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Association of SORL1 alleles with late-onset Alzheimer's Disease. Findings from the GIGAS_LOAD study and mega-analysis
Olgiati  P, Politis  A, Albani D, Rodilossi S, Polito L,  Ateri E, Zisaki A, Piperi C, Liappas I,  Stamouli E, Mailis A, Atti AR, Ferrari B, Morini V, Moretti F, Biella G, Forloni G, Papadimitriou  GN, De Ronchi D,  Kalofoutis A and Serretti A
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00070]

The pathophysiology of Alzheimer's disease (AD) is influenced by sorting-protein related receptor (sorLa) that is less expressed in AD patients. The gene encoding sorLa (SORL1) has been investigated as a susceptibility factor for late-onset AD (LOAD) with conflicting results. Our objectives were to confirm the association between SORL1 SNPsand LOAD in two independent South-European centers and to perform a mega-analysis of published samples. We analyzed three SORL1 SNPs (intron 6: rs668387; rs689021; rs641120)  from the Greece-Italy Genetic Association Study on late-onset AD (GIGAS_LOAD). Greek sample included 96 patients with LOAD (DSM-IV) and 120 unrelated controls. In Italy, a community-based sample is ongoing. 47 LOAD patients and 165 controls were recruited until study endpoint. These samples and previously published ones (Alzgene) were pooled as in a single study. A test for trend was used to analyze genotype association. In the GIGAS_LOAD sample no association was detected between SORL1 genotypesand LOAD. Conversely all SNPs were associated with LOAD in mega-analysis based on ordinal classification of genotypes (Armitage's test: p<0.001).  Although our analysis of pooled samples has positive results for the association between SORL1 and AD, there is substantial heterogeneity across studies. Thus further examination into SORL1 SNPs and the population  is necessary to determine the role of SORL1 in LOAD.
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Tissue Distribution and Pharmacodynamics of Rivastigmine after Intranasal and Intravenous Administration in Rats
Yang Z-Z, Zhang Y-Q, Wu K, Wang  Z-Z and Qi X-R
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00071]

The aim of the study was mainly to investigate the relationship between concentration of rivastigmine and its inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) following intranasal (IN) and intravenous (IV) administration in rats, and to provide a novel nasal delivery route for the brain disease therapy. Rivastigmine was administered to male rats at 2 mg/kg by IN and IV route. Drug concentration, AChE and BuChE activity were measured in the plasma, central nervous system (CNS) regions i.e. olfactory region, hippocampus, cerebrum and cerebellum, and peripheral tissues. It was determined that rivastigmine was characterized by extremely rapid and complete absorption into the systemic circulation followed by a rapid decline in the plasma concentrations, and can also quickly distribute into CNS and peripheral tissues by the two routes. IN administration showed higher concentration in CNS regions and longer action on inhibiting the activity of AChE and BuChE than IV administration. More significant decrease of the two enzymes was observed in CNS regions than in peripheral tissues for both administrations. A close relationship was found between the concentration of rivastigmine and enzyme inhibition in plasma and CNS tissues in rats. Based on these findings, it was concluded that rivastigmine could cause relatively strong inhibition of AChE and BuChE in plasma and brain tissues, especially in hippocampus, cortex and cerebrum. The pharmacodynamics was closely related to its concentration in vivo. The intranasal route can be strategy for delivering the drug into brain.
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Deciphering the Physiology Underlying the Rapid Clinical Effects of Perispinal Etanercept in Alzheimer’s Disease
Edward Tobinick
[Purchase Article] [PMID: 22191562 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00072]

Excess tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of Alzheimer’s disease(AD). Clinical improvement following perispinal administration of etanercept in patients with Alzheimer’s disease and other forms of dementia and brain dysfunction is characteristically evident within minutes. The rapidity and constellation of the clinical effects across multiple domains (cognition, mood, memory, motor function, and attention) suggest they are mediated by non-synaptic signaling mechanisms previously unrecognized for etanercept. These mechanisms likely extend beyond the known roles of TNF as a gliotransmitter that modulates synaptic strength, synaptic scaling, and AMPA receptor trafficking. Preliminary basic science and clinical investigation suggests that perispinal administration of etanercept may lead to its rapid penetration into the cerebrospinal fluid (CSF) within the cerebral ventricles. Diffusion of large molecules into the periventricular brain parenchyma is known to occur, but this process may not be sufficient to explain the rapidity of the clinical effects. There exist populations of cells, including CSF-contacting neurons and modified ependymal cells called tanycytes, that have receptive surfaces in direct contact with the CSF. It is hypothesized that the rapid clinical effects of perispinal etanercept involve non-synaptic signal transduction across the ependymal barrier and into neuronal networks via these CSF-contacting cells. This hypothesis challenges the dogma that penetration of a therapeutic into the cerebral parenchyma through the endothelium of the cerebral vasculature (the so-called blood- brain barrier) is necessary to produce rapid clinical effects in AD. CSF-contacting cells may constitute a therapeutic target for a diverse group of brain, psychiatric and spinal disorders.
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Galantamine-based hybrid molecules with acetylcholinesterase, butyrylcholinesterase and γ-secretase inhibition activities
Vezenkova L, Sevalle J, Danalev D, Ivanov T, Bakalova A, Georgieva M and Checler F
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00073]

We previously designed novel peptides-containing galantamine analogues. These compounds we analyzed for their putative inhibitory effect towards acetylcholinesterase, butyrylcholinesterase and γ-secretase, three activities of which could be central to various neurodegenerative pathologies including Alzheimer's disease. These pharmacological agents were virtually equipotent on acetylcholinesterase activity but display drastically higher inhibitory activities towards butyrylcholinesterase with several compounds displaying an about 100-fold higher activity than that harboured by galantamine. Strikingly, two of the galantamine amides that displayed low activity towards acetylcholinesterase exhibited the highest inhibitory potency towards butyrylcholinesterase (106 to 133 times more active than galantamine). Interestingly, five compounds show a rather good γ-secretase inhibitory potency while they retain their ability to inhibit AChE and/or BuChE activity. Thus, we have been able to design novel compounds with significant inhibitory activity against several of the enzymes responsible for key dysfunctions taking place in several neurodegenerative diseases. These mixed inhibitors could therefore be envisioned as potential pharmacological tools aimed at circumventing the degenerative processes taking place in these major pathologies.
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Disturbed sleep patterns in elders with mild cognitive impairment: The role of memory decline and ApoE ε4 genotype
Hita-Yañez E, Atienza M, Gil-Neciga E and Cantero JL
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00074]

Sleep disturbances are prevalent in patients with Alzheimer’s disease (AD), being one of the most troubling symptoms during the progression of disease. However, little effort has been devoted to determine if impaired sleep patterns appear years before AD diagnosis is made. This study tries to shed light on this issue by performing polysomnographic recordings in healthy elders and patients with mild cognitive impairment (MCI). We further investigated whether changes in sleep patterns parallel memory decline as well as its relationship with the Apolipoprotein E (ApoE) ε4 genotype. Results showed a significant shortening of rapid eye movement (REM) sleep together with increased fragmentations of slow-wave sleep in MCI patients relative to healthy elders. Interestingly, results also revealed that reduction of REM sleep in MCI patients with ApoE ε 4 was more noticeable than in ε4 non-carriers. Contrary to our initial hypothesis, changes in sleep patterns were not correlated with memory performance in MCI patients. Instead, increased REM sleep accompanied enhanced immediate recall in MCI ε 4 non-carriers. Taken together, these results suggest that sleep disruptions are evident years before diagnosis of AD, which may have implications for early detection of dementia and/or therapeutic management of sleep complaints in MCI patients.
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Effects of Cholinergic Enhancing Drugs on Cholinergic Transporters in the Brain and Peripheral Blood Lymphocytes of Spontaneously Hypertensive Rats
Tomassoni D, Catalani A, Cinque C, Antonietta di Tullio M, Tayebati SK, Cadoni A, Nwankwo IE, Traini E and Amenta F
[Purchase Article] [PMID: 22191561 PubMed - indexed for MEDLINE] [BSP/CAR/E-Pub/00075]

Cholinergic hypofunction is a trait of Alzheimer’s disease and vascular dementia and countering it is one of the main therapeutic strategies available for these disorders. Cholinergic transporters control cellular mechanisms of acetylcholine (ACh) synthesis and release at presynaptic terminals. This study has assessed the influence of 4 week treatment with two different cholinergic enhancing drugs, the cholinergic precursor choline alphoscerate (alpha-glycerylphosphorylcholine) or the acetylcholinesterase (AChE) inhibitor galantamine on high affinity choline uptake transporter (CHT) and vesicular ACh transporter (VAChT) expression in the brain of spontaneously hypertensive rats (SHR). SHR represent an animal model of cerebrovascular injury characterized by cholinergic hypofunction. Analysis was performed by immunochemistry, ELISA and immunohistochemistry on frontal cortex, striatum and hippocampus. Immunochemical and ELISA analysis was extended to peripheral blood lymphocytes (PBL), used as a peripheral reference of changes of brain cholinergic markers. An increased expression of VAChT and CHT was observed in brain areas investigated and in PBL of SHR. The similar trend for cholinergic transporters observed in brain and PBL suggests these cells may represent a marker of brain cholinergic transporters. Treatment with choline alphoscerate increased CHT and to a greater extent VAChT expression. Treatment with galantamine countered the increase of CHT and VAChT. The different activity of the cholinergic precursor and of the AChE inhibitor on parameters investigated is likely related to their mechanism of action. Choline alphoscerate increases ACh synthesis and release. This requires an augmentation of systems regulating neurotransmitter uptake and storage. The effect of choline alphoscerate on CHT and VAChT observed in this study suggests an improved synaptic efficiency elicited by the compound. The AChE inhibitor slows-down ACh degradation in the synaptic cleft. A greater availability of neurotransmitter elicited by galantamine counters the enhanced activity of cholinergic transporters compensating cholinergic deficits. Differences in the activity of the cholinergic precursor and AChE inhibitor investigated on CHT and VAChT suggests that association between choline alphoscerate and AChE/cholinesterase inhibitors may represent a strategy for potentiating deficient cholinergic neurotransmission worthwhile of being investigated in clinical trials.
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Combining Neuropsychological and Structural Neuroimaging Indicators of Conversion to Alzheimer’s Disease in Amnestic Mild Cognitive Impairment
Venneri A, Gorgoglione G, Toraci C, Nocetti L, Panzetti P and Nichelli P
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00076]

Morphometric and neuropsychological retrospective studies of amnestic mild cognitive impairment (MCI) have demonstrated that regional atrophies and cognitive impairments may differentiate stable from progressing MCI. No measure has proved helpful prospectively. In this study, twenty five amnestic MCI patients and 25 healthy controls underwent structural MRI and comprehensive neuropsychological assessment. The groups’ grey matter volumes were compared with voxel based morphometry and were also correlated with scores obtained on paired associates learning and category fluency tasks. MCI patients had significantly reduced grey matter volume in left mediotemporal and other neocortical regions compared to controls. Atrophy in perirhinal and anterior inferior temporal cortex was associated with poor scores on both category fluency and paired associates learning tasks. After 36 months, 44% of the MCI sample converted to dementia. Converter and non-converter MCI subgroups differed in paired associates learning and in category fluency scores, and showed limited differences in grey matter loss in the hippocampal complex. Variable atrophy in the hippocampus was not a relevant element in the converter/non converter distinction, but converters had significant volumetric reductions in the perhirinal cortex and in other anterior temporal and frontal neocortical areas. A high proportion of converters (91%) could be identified from baseline data using a combination of measures of regional atrophy in left temporal association cortex and poor scores on paired associates learning and category fluency tasks. This combined approach may offer a better option than using each measure alone to prospectively identify individuals at more immediate risk of conversion to dementia in the MCI population. The clinical advantage of this combination of structural MRI and neuropsychological measures in predicting conversion to dementia will need additional prospective validation.
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Evolution of global and local grey matter atrophy on serial MRI scans during the progression from MCI to AD
Spulber G, Niskanen E, MacDonald S, Kivipelto M, Padilla DF, Julkunen V, Hallikainen M, Vanninen R, Wahlund L-O and Soininen H
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00077]

Mild cognitive impairment (MCI) often represents a prodromal form of dementia, conferring a significantly higher risk of converting to probable Alzheimer's disease (AD). The aim of this study is to characterise the differences of grey matter (GM) distribution and dynamics between progressive and stable MCI subjects during a 2 year period preceding the conversion to AD. We included 48 stable MCI and 12 progressive MCI cases based on the availability of 3 serial scans acquired with approximately 1 year scan interval. For the progressive MCI group, the third scan was acquired at the time of the clinical diagnosis of AD, while the first two scans were acquired approximately 2 and 1 years earlier. For the stable MCI group, the three scans were acquired at approximately 1 year intervals during a period free from significant cognitive decline. We used longitudinal voxel-based morphometry (VBM) for mapping the progression of GM loss over time. For the progressive MCI group, the cross-sectional analysis revealed areas of lower GM volumes in the parahippocampal gyrus, precuneus and posterior cingulate 12 months before the AD diagnosis. For the longitudinal VBM analysis the progressive MCI group revealed increased GM loss in cortical regions belonging to the temporal neocortex, parahippocampal cortex, and cingulate gyrus. The frontal lobe, insula and the cerebellum were also affected. This accelerated atrophy may offer new insights into the understanding of neurodegenerative pathology and the clinical relevance of these changes remains to be verified by subsequent studies.
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Gender-dependent levels of hyaluronic acid in cerebrospinal fluid of patients with neurodegenerative dementia
Henrietta M Nielsen, Sebastian Palmqvist, Lennart Minthon, Elisabet Londos and Malin Wennström
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00078]

Numerous reports over the years have described neuroinflammatory events and vascular changes in neurodegenerative diseases such as Alzheimers disease (AD) and
dementia with Lewy bodies (DLB). Interestingly, recent reports from other research areas suggest that the inflammatory and vascular processes are influenced by gender.

These findings are intriguing from the perspective that women show a higher incidence of AD and warrant investigations on how gender influences various processes in neurodegenerative dementia. In the current study we measured the cerebrospinal fluid (CSF) and plasma concentrations of hyaluroinic acid (HA), an adhesionmolecule known to regulate both vascular and inflammatory processes, in AD and DLB patients as well as in healthy elders. Our analysis showed that male AD and DLB patients had almost double the amount of HA compared to female patients whereas no gender differences was observed in the controls. Furthermore, we found that CSF levels of HA in foremost female AD patients correlated with various AD related biomarkers. Correlations between HA levels and markers of inflammation and vascular changes were only detected in female AD patients but in both male and female DLB patients. We conclude that HA may be linked to several pathological events present in AD, as reflected in CSF protein concentrations. The HA profile in CSF, but not in plasma, and associations to other markers appear to be genderdependent which should be taken into account in clinical examinations and future biomarker studies.
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Threshold-independent meta-analysis of Alzheimer`s disease transcriptomes shows progressive changes in hippocampal functions, epigenetics and microRNA regulation
Barbash S and Soreq H
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00079]

End-stage Alzheimer`s disease (AD) involves drastic modifications in neuronal molecular and cellular processes, but little is known about the dynamics of these modifications during disease initiation and progression. Here, we report meta-analysis of 100 publicly available Microarray datasets using threshold-independent analysis. We found that different patients react to AD progression by variable single transcript alterations which however lead to similar changes in functional gene groups. Stratification by patients' cognitive deterioration presented hippocampal-specific mRNA alterations which involved progressively changed gene categories and indicate changes in epigenetic state and microRNA profiles. In addition, datasets from laser-captured neurofibrillary tangles-free hippocampal neurons and transcript classification by cell types identified many of these changes in neurons. Intriguingly, we discovered that early-onset decline in alternative splicing, protein folding and transport transcripts occur concurrently with decreases in synaptic transmission, whereas at later stages these changes progressed into enhanced oxidative stress and inflammation. Our findings open new venues for identifying novel targets for intervention with AD progression.
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Cognitive Abilities of Alzheimer’s Disease Transgenic Mice are Modulated by Social Context and Circadian Rhythm
Kiryk  A, Mochol G, Filipkowski RK, Wawrzyniak M, Lioudyno V, Knapska E, Gorkiewicz T, Balcerzyk M, Leski S, Leuven  FV, Lipp H-P, Wojcik DK and Kaczmarek L
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00080]

In the present study, we used a new training paradigm in the intelliCage automatic behavioral assessment system to investigate cognitive functions of the transgenic mice harboring London mutation of the human amyloid precursor protein (APP.V717I). Three groups of animals: 5-, 12- and 18-24-month old were subjected to both Water Maze training and the IntelliCage-based appetitive conditioning. The spatial memory deficit was observed in all three groups of transgenic mice in both behavioral paradigms. However, the APP mice were capable to learn normally when co-housed with the wild-type (WT) littermates, in contrast to clearly impaired learning observed when the transgenic mice were housed alone. Furthermore, in the transgenic mice kept in the Intellicage alone, the cognitive deficit of the young animals was modulated by the circadian rhythm, namely was prominent only during the active phase of the day. The novel approach to study the transgenic mice cognitive abilities presented in this paper offers new insight into cognitive dysfunctions of the Alzheimer’s disease mouse model.
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Effects of the Putative Cognitive-Enhancing Ampakine, CX717, on Attention and Object Recognition Memory
Zheng Y, Balabhadrapatruni S, Masumura C, Darlington CL and Smith PF
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00081]

Ampakines are a class of putative nootropic drug designed to positively modulate the AMPA receptor and have been investigated as a potential treatment for cognitive disorders such as Alzheimer’s Disease. Nonetheless, some ampakines such as CX717 have been incompletely characterized in behavioural pharmacological studies. Therefore, in this study, we attempted to further characterize the effects of the ampakine, CX717 (20 mg/kg s.c), on the performance of rats in a 5 choice serial reaction time (5CSRTT) and object recognition memory task, using rats with cognitive deficits caused by bilateral vestibular deafferentation (BVD) as a model. In the 5CSRTT, when the stimulus duration was varied from 5 to 2 sec, the number of incorrect responses was significantly greater for the BVD group compared to sham controls, but significantly less for the CX717 groups, with no significant interaction. With changes in inter-trial interval (ITI), there was a significant effect of surgery/drug and a significant effect of ITI on premature responses, and the BVD group treated with CX717 showed significantly fewer premature responses than the other groups. In the object recognition memory task, CX717 significantly reduced total exploration time and the exploration towards the novel object in both sham and BVD animals. These results suggest that CX717 can reduce the number of incorrect responses in both sham and BVD rats and enhance inhibitory control specifically in BVD rats, in the 5CSRTT. On the other hand, CX717 produced a detrimental effect in the object recognition memory task.
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Trehalose protects from aggravation of amyloid pathology induced by isoflurane anesthesia in APP_swe mutant mice
Perucho J, Casarejos MJ, Gomez A, Solano RM, Garcia de Yébenes J and Mena MA
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00082]

There is an open controversy about the role of surgery and anesthesia in the pathogenesis of Alzheimer’s disease (AD). Clinical studies have shown a high prevalence of these procedures in subjects with AD but the interpretation of these studies is difficult because of the co-existence of multiple variables. Experimental studies in vitro and in vivo have shown that small molecular weight volatile anesthetics enhance amyloidogenesis in vitro and produce behavioral deficits and brain lesions similar to those found in patients with AD.

We examined the effect of co-treatment with trehalose on isoflurane-induced amyloidogenesis in mice. WT and APPswe mice, of 11 months of age, were exposed to 1% isoflurane, 3 times, for 1.5 hours each time and sacrificed 24 hours after their last exposure to isoflurane. The right hemi-brain was used for histological analysis and the contra-lateral hemi-brain used for biochemical studies.

In this study, we have shown that repetitive exposure to isoflurane in pre-symptomatic mature APPswe mice increases apoptosis in hippocampus and cerebral cortex, enhances astrogliosis and the expression of GFAP and that these effects are prevented by co-treatment with trehalose, a disaccharide with known effects as enhancer of autophagy. We have also confirmed that in our model the co-treatment with trehalose increases the expression of autophagic markers as well as the expression of chaperones. Co-treatment with trehalose reduces the levels of β amyloid peptide aggregates, tau plaques and levels of phospho-tau. Our study, therefore, provides new therapeutic avenues that could help to prevent the putative pro-amyloidogenic properties of small volatile anesthetics.
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Granular Non-fibrillar Aggregates and Toxicity in Alzheimer’s Disease
Benseny-Cases N, Klementieva O, Malý J and Cladera J
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00083]

Granular non-fibrillar aggregates (GNAs) are identified as possible toxic species in Alzheimer’s disease. GNAs form on the surface of negatively charged biological membranes and as a consequence of an acidic environment, off the polymerization pathway at neutral pH. Aβ(1-40) GNAs disturb the bilayer structure of model membranes and seem to be more toxic to cells with negatively charged membranes (consequence of chronic pre-apoptosis). GNAs may be relevant in physiological situations associated to Alzheimer’s disease: a local acidic pH at the cell surface (consequence of lipid oxidation or other cell insults) and acidification as a consequence of vascular events causing hypoxia. Together with previous descriptions of granular aggregates with poly-glutamine peptides related to Huntington’s disease and the SH3 domain of PI3, GNAs related to Alzheimer’s disease are a further example of a possible common aggregation and toxicity mechanism in conformational diseases. GNAs may represent a new pharmacological target in Alzheimer’s disease.
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The association of ACT -17 A/T polymorphism with Alzheimer’s disease: a meta-analysis
Dou C, Zhang J, Sun Y, Zhao X, Wu Q, Ji C, Gu S, Xie Y and Mao Y
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00084]

Association studies between Alpha-1-antichymotrypsin (ACT)-17(A>T) polymorphisms and Alzheimer‟s disease (AD) susceptibility have shown conflicting results. In this investigation, we performed a meta-analysis to assess the purported associations. Subgroup analyses based on ethnicity (Caucasians, East-Asian and American mixed) were also performed including a total of 5,676 AD patients and 5,460 controls for ACT-17. Overall, allele contrast (A vs. T) of ACT -17 polymorphism produced significant results in the worldwide population [Pheterogeneity=0.01, random-effects (RE) odds ratio (OR) 1.12; 95% CI 1.04-1.21, P=0.003] and in the Caucasian population [Pheterogeneity=0.03, RE OR1.11 95% CI 1.01-1.24, P=0.04]. Meta-analyses of other genetic contrasts suggested that the A allele carriers are associated with increased susceptibility to AD in variant populations. No significant association was observed in the East-Asian subgroup analysis. In conclusion, ACT-17 variation presents a risk factor for AD in the worldwide population, especially in the Caucasian population.
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Allopregnanolone Increases the Number of Dopaminergic Neurons in Substantia Nigra of Triple Transgenic Mouse Model of Alzheimer’s Disease
Sun C, Ou X, Farley JM, Stockmeier C, Bigler S, Brinton RD and Wang JM
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00085]

More than one-third of Alzheimer’s disease (AD) patients show nigrostriatal pathway disturbances, resulting in akinesia (inability to initiate movement) and akathisia (inability to remain motionless). The high prevalence of this dysfunction of dopaminergic neuron in the nigrostriatal pathway in AD suggests that AD is a significant risk factor for substantia nigra pars compacta (SNpc) lesions. Previously, we have demonstrated that allopregnanolone (APα) promotes neurogenesis and improves the cognitive function in a triple transgenic mouse model of AD (3xTgAD). In this study, we sought to exam 1) the SNpc lesions in 3xTgAD mice and 2) the impact of APα on promoting the regeneration of new dopaminergic neurons in SNpc of 3xTgAD mice. The number of Nissl-stained total neurons, tyrosine hydroxylase (TH) positive neurons, and BrdU/TH double positive newly formed neurons were analyzed with unbiased stereology. In the SNpc of 3xTgAD mice, TH positive neurons was 47 ± 18 % (p = 0.007), total neurons was 62 ± 11.6 % (p = 0.016), of those in the SNpc of non-Tg mice, respectively. APα treatment increased the TH positive neurons in the SNpc of 3xtgAD mice to 93.2 ± 18.5 % (p = 0.021 vs. 3xTgAD vehicle) and the total neurons to 84.9 ± 6.6 (p = 0.046 vs. 3xTgAD vehicle) of non-Tg mice. These findings indicate that there is a loss of neurons, specifically the TH positive neurons in SNpc of 3xTgAD mice, and that APα reverses the lesion in SNpc of 3xTgAD by increasing the formation of new TH neurons.
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Pilot Randomized Controlled Study of a Histamine Receptor Inverse Agonist in the Symptomatic Treatment of AD
Egan M, Yaari R, Liu L, Ryan M, Peng Y, Lines C and Michelson D
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00086]

We performed a clinical trial to evaluate the effects of the histamine subtype-3 receptor inverse agonist MK-0249 on cognition in AD patients. Mild-to-moderate AD patients were randomized 1:1 to 4 weeks of double-blind daily treatment with oral MK-0249 5-mg or placebo. Pharmacokinetic and PET data suggested that MK-0249 5-mg daily would achieve approximately 85% brain receptor occupancy at Cmax in elderly patients. Primary efficacy measures were the short Computerized-Neuropsychological- Test-Battery (CNTB) Summary Score and ADAS-Cog score. A secondary efficacy measure was a Cognition Summary Score summarizing results from 7 cognitive tests. Of 144 patients randomized, 132 completed 4 weeks (MK-0249 = 65, placebo = 67). Most patients (88.2%) were on concomitant symptomatic AD treatment. There were no significant differences between treatments on primary and secondary endpoints at week 4: short CNTB Summary Score = 0.89 (95% CI: -0.74,2.52); ADAS-Cog score = -0.25 (95% CI: -1.61,1.11); Cognition Summary Score = 1.38 (95% CI: -0.64,3.40). MK-0249 was generally well tolerated but was associated with an increased percentage of patients with adverse events (41/73; 56.2%) versus placebo (18/70; 25.7%). Adverse events in >5% of patients on MK-0249 were diarrhea (8.2% vs. 2.9%), headache (8.2% vs. 1.4%), muscle spasms (5.5% vs. 0%), insomnia (5.5% vs. 0%) and stomach discomfort (5.5% vs. 0%). MK-0249 5-mg once daily over 4 weeks was not effective in improving cognitive function in mild to moderate AD patients who were on concomitant symptomatic AD treatment.
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Neurosteroid PREGS protects neurite growth and survival of newborn neurons in the hippocampal dentate gyrus of APPswe/PS1dE9 mice
Xu B, Yang R, Chang F, Chen L, Xie G, Sokabe M and Chen L
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00087]

Neurosteroids pregnenolone-sulfate (PREGS) and dehydroepiandrosterone (DHEA) have been shown to enhance neurogenesis in the hippocampal dentate gyrus (DG) of adult rodents. In Alzheimer’s disease (AD) brain, the levels of these neurosteroids are known to be altered compared to age-matched non-demented controls. The aim of this study was to examine the effects of PREGS and DHEA on the hippocampal neurogenesis in 8-month-old male APPswe/PS1dE9 transgenic (APP/PS1) mice that show amyloid plaques and impaired spatial cognitive performance. In the DG of APP/PS1 mice the proliferation of progenitor cells was increased, while the neurite growth and survival of newborn neuronal cells were markedly impaired. Treatment with PREGS or DHEA rescued perfectly the hypoplastic neurite of newborn neurons in APP/PS1 mice, while neither of them affected the over-proliferation of progenitor cells. Notably, the administration of PREGS, but not DHEA, to APP/PS1 mice could protect the survival and maturation of newborn neuronal cells, which was accompanied with the improvement of spatial cognitive performance. The results indicate that treatment of AD like brains of APP/PS1 mice with PREGS might protect the hippocampal neurogenesis, leading to the improved spatial cognitive performance.
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White Matter Damage along the Uncinate Fasciculus Contributes to Cognitive Decline in AD and DLB
Serra L, Cercignani M, Basile B, Spanò B, Perri R, Fadda L, Marra C, Giubilei F, Caltagirone C and Bozzali M
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00088]

This study investigates the patho-physiological implications of the uncinate fasciculus (UF) in the two most common forms of dementia, namely Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Forty-five consecutive patients diagnosed with either probable AD or DLB, and 16 individuals with amnesic mild cognitive impairment (a-MCI) were investigated using diffusion tensor MRI. Thirteen healthy subjects (HS) were also studied as controls. In each subject, the UF was bilaterally reconstructed by probabilistic tractography. From each UF, macroscopic volume and correspondent fractional anisotropy (FA) (an index of microscopic white matter integrity) were derived for the whole tract, and for the frontal and temporal portion of the UF. No significant between-group volumetric differences were found. In contrast, FA values from the UF were reduced bilaterally in patients with dementia (either AD or DLB) compared to HS. In addition, patients with AD showed reduced FA values compared to those with a-MCI. No significant FA difference was found between AD and DLB patients, nor between a-MCI and HS. Finally, in all patients, UF FA values were associated with neuropsychological scores at tests exploring memory and executive functions. This study indicates that the UF is remarkably damaged in patients at the stage of dementia, independently from the diagnostic form. Moreover, this UF damage seems to be driven by temporal involvement in AD, for which a prodromal stage (a-MCI) is defined.
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Low-dose Radiation Stimulates Wnt/β-catenin Signaling, Neural Stem Cell Proliferation and Neurogenesis of the Mouse Hippocampus in vitro and in vivo
Wei L-C, Ding Y-X, Liu Y-H, Duan L, Bai Y, Shi M and Chen L-W
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00089]

Neurogenesis in the hippocampus is actively involved in neural circuit plasticity and learning function of mammals, but it may decrease dramatically with aging and aging-related neurodegenerative disorder Alzheimer’s disease. Accumulating studies have indicated that Wnt/β-catenin signaling is critical in control of proliferation and differentiation fate of neural stem cells or progenitors in the hippocampus. In this study, the biological effects of low-dose radiation in stimulating Wnt/β-catenin signaling, neural stem cell proliferation and neurogenesis of hippocampus were interestingly identified by in vitro cell culture and in vivo animal studies. First, low-dose radiation (0.3Gy) induced significant increasing of Wnt1, Wnt3a，Wnt5a, and β-catenin expression in both neural stem cells and in situ hippocampus by immunohistochemical and PCR detection. Secondly, low-dose radiation enhanced the neurogenesis of hippocampus indicated by increasing proliferation and neuronal differentiation of neural stem cells, going up of nestin-expressing cells and BrdU-incorporation in hippocampus. Thirdly, it promoted cell survival and reduced apoptotic death of neuronal stem cells by flowcytometry analysis. Finally, Morris water-maze test showed behavioral improvement of animal learning in low-dose radiation group. Accordingly, detrimental influence on Wnt/β-catenin signaling or neurogenesis was confirmed in high-dose radiation (3.0Gy) group. Taken together, this study has revealed certain beneficial effects of low-dose radiation to stimulate neural stem cell proliferation, neurogenesis of hippocampus and animal learning activity most possibly by triggering Wnt/β-catenin signaling cascades, suggesting its translational application role in devising new therapy for aging-related neurodegenerative disorders particularly Alzheimer’s disease.
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Common variants in toll-like receptor 4 confer susceptibility to Alzheimer’s disease in a Han Chinese population
Yu J-T , Miao D, Cui W-Z, Ou J-R, Tian Y, Wu Z-C, Zhang W and Tan L
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00090]

Toll-like receptor 4 (TLR4) represents a reasonable functional and positional candidate gene for Alzheimer’s disease (AD) as it is located within the previous identified linkage region of AD on chromosome 9q, and functionally is involved in the microglia-mediated inflammatory response, amyloid-β (Aβ) plaque formation and Aβ clearance. To test whether variants in the TLR4 gene are associated with late-onset AD (LOAD), we organized a multicenter study of 785 subjects (399 cases and 386 matched controls) in a Han Chinese population. Ten single nucleotide polymorphisms (SNPs) that span the TLR4 gene, from approximately 5 kb of the predicted 5’-untranslated region (UTR) to approximately 6 kb of the predicted 3’- UTR, were selected and their associations with LOAD risk factors were assessed. With respect to allelic diversity, the minor alleles of seven SNPs (rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, rs7037117, and rs7045953) in TLR4 showed consistent protective effects against the risk of developing LOAD. With regard to genotypic diversity, individuals carrying at least one minor allele of each SNP above had a consistently lower risk of LOAD than those with no copies of the minor alleles (ORs ranging from 0.445 to 0.637). rs7045953, located in the 3’-UTR of TLR4, was most strongly associated with LOAD, and when incorporated into a haplotype with rs10759930, the strongest association was detected (P = 1.7×10-6, Pc =1.0×10-4). Our data suggests that the TLR4 gene contributes to the susceptibility for LOAD in Han Chinese.
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Pharmacological inhibition of PKR in APPswePS1dE9 mice transiently prevents inflammation at 12 months of age but increases Aβ42 levels in the late stages of the Alzheimer’s disease
Couturier J, Paccalin M, Lafay-Chebassier C, Chalon S, Ingrand I, Pinguet J, Pontcharraud R, Guillard O, Fauconneau B and Page G
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00091]

The double-stranded RNA-dependent protein kinase (PKR) is switched on by a wide range of stimuli, including the amyloid peptide. Then, PKR transmits signals to the translational machinery, apoptosis and inflammatory signaling pathways by interacting with some adapters. In virus-infected cells, PKR engages the nucleus factor κB (NF-κB) pathway. In many models of Alzheimer’s disease (AD) and patients with AD, PKR was activated. Furthermore, there is strong evidence implicating the inflammatory process in the AD brain. However, the PKR involvement in inflammatory responses in AD is not elucidated. Based on our previous in vitro results, the aim of this study was to evaluate the effects of a pharmacological inhibition of PKR in inflammation in APPswePS1dE9 transgenic mice. Our results showed that PKR inhibition prevented the NF-κB activation and production of tumor necrosis factor alpha (TNFα) and interleukin (IL)-1β at 12 months of age without decrease of Aβ42 levels and memory deficits. Surprisingly, PKR inhibition failed to prevent IL-1β-mediated inflammation and induced a great increase in β-amyloid peptide (Aβ42) levels at 18 months of age. In this model, our findings highlight the lack of relationship between inflammation and Aβ42 levels. Moreover, the age-dependent inflammatory response must be carefully taken into account in the establishment of an anti-inflammatory therapy in AD.
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Hippocampal BDNF Expression in a Tau Transgenic Mouse Model
Burnouf S, Belarbi K, Troquier L, Derisbourg M, Demeyer D, Leboucher A, Laurent C, Hamdane M, Buee L and Blum D
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00092]

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by extracellular accumulation of amyloid deposits and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated Tau proteins. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor playing a critical role in hippocampal synaptic plasticity and memory and whose levels have been shown reduced in AD brains. While recent data support a pivotal role of β-amyloid peptides towards BDNF decrease, whether Tau pathology impacts on BDNF expression remains unknown so far. In the present study, we have evaluated this relationship using quantitative PCR, Western blot and ELISA in the THY-Tau22 transgenic strain, known to display a progressive development of both hippocampal AD-like Tau pathology and memory impairments. We observed that Tau pathology was not associated with down-regulation of BDNF at the protein and mRNA levels in this model, suggesting that the alteration of BDNF homeostasis observed in AD patients’ brains might rather be ascribed to amyloid pathology.
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UBQ-8i polymorphism is not an independent risk factor for mild cognitive impairment and Alzheimer’s disease in APOE-4 carriers
Elcoroaristizabal Martín X, Fernández Martínez M, Gamarra Fernandez D, Gómez Busto F, Galdos Alcelay L, Calzada Ferreras MJ, Castro Flores J and de Pancorbo M
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00093]

Background: Alzheimer’s disease (AD) has a complex genetic etiology, and as a result many genes have been studied to determine how they might be involved with the disease. Amyloidogenic effects have been broadly linked with familial forms of the disease, though certain genes such as UBQLN1 could also play a role in prodromal phases such as amnesic mild cognitive impairment (MCI).

Aim: The aim of this study is to examine the role of the UBQ-8i (rs12344615) functional polymorphism in the UBQLN1 gene as a risk factor for MCI and AD and its possible synergies with apolipoprotein gene E (APOE).

MATERIAL & METHODS: 215 MCI patients, 347 sporadic AD sufferers and 238 healthy controls from the Basque Country (Spain) were analysed. Clinical criteria and neuro-psychiatric tests were used to establish the diagnostic groups. SNP, UBQ-8i and the APOE gene were genotyped via real-time polymerase chain reaction (rtPCR), polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLPs) respectively. Multinomial logistic regression models were used to determine the risk for MCI and AD.

RESULTS: Allele C of rs12344615 of the UBQLN1 gene is not a risk factor for MCI or AD (OR = 0.88, CI95% 0.60-1.31 p=0.542 and OR = 0.73, CI95% 0.51-1.02 p=0.079, respectively). Moreover, genotypes with at least one C allele are observed not to show synergies with APOE*E4 in MCI or with AD sufferers.

CONCLUSION: Allele C of polymorphism UBQ-8i of the UBQLN1 gene is not an independent risk factor for MCI or AD. Moreover, this allele is not observed to have any synergy effects with APOE*E4.
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Targeting phospho-Ser422 by active Tau immunotherapy in the THY-Tau22 mouse model: a suitable therapeutic approach
Troquier L, Caillierez R, Burnouf S, Fernandez-Gomez FJ, Grosjean M-J, Zommer N, Sergeant N, Schraen-Maschke S, Blum D and Buee L
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00094]}

Recent data indicate that Tau immunotherapy may be relevant for interfering with neurofibrillary degeneration in Alzheimer disease and related disorders referred to as Tauopathies. The key question for immunotherapy is the choice of the epitope to target. Abnormal phosphorylation is a well-described posttranslational modification of Tau proteins and may be a good target. In the present study, we investigated the effects of active immunization against the pathological epitope phospho-Ser422 in the THY-Tau22 transgenic mouse model. Starting from 3-6 months of age, THY-Tau22 mice develop hippocampal neurofibrillary tangle-like inclusions and exhibit phosphorylation of Tau on several AD-relevant Tau epitopes. Three month-old THY-Tau22 mice were immunized with a peptide including the phosphoserine 422 residue while control mice received the adjuvant alone. A specific antibody response against the phospho-Ser422 epitope was observed. We noticed a decrease in insoluble Tau species (AT100- and pS422 immunoreactive) by both biochemical and immunohistochemical means correlated with  significant cognitive improvement using the Y-maze. This Tau immunotherapy may facilitate Tau clearance from the brain toward the periphery since, following immunization, an increase in Tau concentrations was observed in blood. Overall, the present work is, to our knowledge, the first one to demonstrate that active immunotherapy targeting a real pathological epitope such as phospho-Ser422 epitope is efficient. This immunotherapy allows for Tau clearance and improves cognitive deficits promoted by Tau pathology in a well-defined Tau transgenic model.
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Roles of Glycogen synthase kinase 3 in Alzheimer’s disease
Cai Z, Zhao Y and Zhao B
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00095]

Evidence from basic molecular biology has noted a critical role of GSK-3 in Alzheimer’s disease (AD) pathogenesis such as beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangle (NFT), and neuronal degeneration. Aβ generation and deposition represents a key feature and is generated from APP by the sequential actions of two proteolytic enzymes: β -secretase and γ-secretase. GSK-3 could play a critical role in Aβ production via enhancing β-secretase activity. GSK-3 not only modulates APP processing in the process of Aβ generation, but regulates Aβ production by interfering with APP cleavage at the γ-secretase complex step since the APP and PS1 (a component of γ-secretase complex) are substrates of GSK-3 as well. GSK-3 may downregulate α-secretase through PKC and ADAMs which are the substrates of GSK-3 contributing to Aβ production. Meanwhile, Aβ accumulation can induce GSK-3 activation through Aβ-mediated neuroinflammation and oxidative stress. Considering that active GSK-3 and some common GSK-3-shared factors induce the hyperphosphorylation of tau and neurofibrillary lesions, GSK-3 is a possible linking between amyloid plaques and NFT pathology. Additionally, GSK-3 could disrupt acetylcholine activity, and accelerate axon degeneration and failures in axonal transport, and lead to cognitive impairment in AD. Preclinical and clinical studies have supported that GSK-3β inhibitors could be useful in the treatment of AD. Thus, an effective measure to inhibit GSK-3 activity may be a very attractive drug target in AD.
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In vivo uptake of β-amyloid by non-plaque associated microglia
Hawkes CA, Deng L, Fenili D, Nitz M and McLaurin J
[Purchase Article] [BSP/CAR/E-Pub/00096]

The role of microglia in β-amyloid (Aβ deposition or clearance in the Alzheimer’s disease (AD) brain remains unclear.  Previous in vivo studies have focused primarily on the association of microglia with Aβ-positive parenchymal plaques, but have given little consideration to the possible interaction between Aβ and non-plaque associated microglia.  Further, it is not known if microglia play a direct role in mediating Aβ uptake following anti-aggregant treatment.  We report here the identification of Aβ-positive processes throughout the cortex and hippocampus of TgCRND8 mice expressing the human Swedish (KM670/671NL) and Indiana (V717F) amyloid precursor protein mutations, which localized to ionized calcium binding protein-1-positive resident microglia that were not associated with extracellular plaques.  Oral administration of 1-deoxy-1-fluoro-scyllo-inositol, a scyllo-inositol analogue, to TgCRND8 mice improved spatial memory impairments and suppressed amyloid pathology in a dose-dependent manner.  Further, treatment with 1-deoxy-1-fluoro-scyllo-inositol significantly increased hippocampal intra-microglial Aβ levels without stimulating microglial proliferation or peripheral macrophage recruitment.  These results reveal a novel, beneficial role for non-plaque associated microglia in the regulation of cerebral Aβ levels in a mouse model of AD.
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Lifestyle and Genetic Contributions to Cognitive Decline and Hippocampal Structure and Function in Healthy Aging
Woodard JL, Sugarman MA, Nielson KA, Smith JC, Seidenberg M, Durgerian S, Butts A, Hantke N, Lancaster M, Matthews MA and Rao SM
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00097]

Background:  Engagement in cognitively stimulating activities (CA) and leisure time physical activity (PA) have been associated with maintaining cognitive performance and reducing the likelihood of cognitive decline in older adults.  However, neural mechanisms underlying protective effects of these lifestyle behaviors are largely unknown.  In the current study, we investigated the effect of self-reported PA and CA on hippocampal volume and semantic processing activation during a fame discrimination task, as measured by functional magnetic resonance imaging (fMRI). We also examined whether possession of the apolipoprotein E (APOE) ε4 allele could moderate the effect of PA or CA on hippocampal structure or function.

METHODS: Seventy-eight healthy, cognitively intact older adults underwent baseline neuropsychological assessment, hippocampal volume measurement via manually-traced structural MRI, and task-activated fMRI. 

RESULTS: After 18 months, 27 participants declined by one standard deviation or more on follow-up neuropsychological testing. Logistic regression analyses revealed that CA alone or in combination with baseline hippocampal structure or functional activity did not predict the probability of cognitive decline. In contrast, PA interacted with APOE ε4 status such that engagement in PA reduced the risk of cognitive decline in APOE ε4 carriers only. Furthermore, the benefits of PA appeared to diminish with reduced functional activity or volume in the hippocampus.

CONCLUSIONS: Our findings suggest that increased leisure time PA is associated with reduced probability of cognitive decline in persons who are at high risk for AD.  The beneficial effects of PA in this group may be related to enhancement of the functional and structural integrity of the hippocampus.
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Relationship between Inflammatory Mediators, Aβ Levels and APOE Genotype in Alzheimer’s Disease
Reale M, Kamal MA , Velluto L, Gambi D, Di Nicola M and Greig NH
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00098]

Activation of inflammatory processes is observed within the brain as well as periphery of subjects with Alzheimer's disease (AD). Whether or not inflammation represents a possible cause of AD or occurs as a consequence of the disease process, or, alternatively, whether the inflammatory response might be beneficial to slow the disease progression remains to be elucidated. The cytokine IL-18 shares with IL-1 the same pro-inflammatory features. Consequent to these similarities, IL-18 and its endogenous inhibitor, IL-18BP, were investigated in the plasma of AD patients versus healthy controls (HC). An imbalance of IL-18 and IL-18BP was observed in AD, with an elevated IL-18/IL-18BP ratio that might be involved in disease pathogenesis. As part of the inflammatory response, altered levels of RANTES, MCP-1 and ICAM-1, molecules involved in cell recruitment to inflammatory sites, were observed in AD. Hence, correlations between IL-18 and other inflammatory plasma markers were analyzed. A negative correlation was observed between IL-18 and IL-18BP in both AD and HC groups. A positive correlation was observed between IL-18 and ICAM-1 in AD patients, whereas a negative correlation was evident in the HC group. IL-18 positively correlated with Aβ in both groups, and no significant correlations were observed between IL-18, RANTES and MCP-1. An important piece of evidence supporting a pathophysiologic role for inflammation in AD is the number of inflammatory mediators that have been found to be differentially regulated in AD patients, and specific ones may provide utility as part of a biomarker panel to not only aid early AD diagnosis, but follow its progression.
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Reviewing the Role of Donepezil in the Treatment of Alzheimer’s Disease
Doody RS, Cummings JL and Farlow MR
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00099]

Donepezil is a reversible, non-competitive piperidine-type acetylcholinesterase inhibitor (AChEI) that is structurally unique compared with other currently available AChEIs. It was developed as a symptomatic treatment to compensate for the progressive loss of cholinergic signal between neurons, a consequence of neuronal cell loss in the brains of patients with Alzheimer’s disease (AD). Clinical trials conducted over the 14 years since the drug was first licensed and available for use in patients with mild to moderate AD (1997) have shown that donepezil is efficacious and well tolerated at all stages of AD, from patients with mild or moderate impairment to those with severe disease. The published literature contains nearly 2000 papers on donepezil, and more than 200 of these articles relate to randomized controlled clinical trials. Trials in patients with mild cognitive impairment (MCI) failed to meet all of their primary objectives, but provided insights into patient selection and the design of trials. Overall, more than a decade of donepezil research has gradually changed attitudes toward therapy of AD from a general belief that no clinically useful treatment exists to the present day understanding that symptomatic therapy may be effective across the spectrum of dementia stages.
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Effects of Atorvastatin on Cerebral Blood Flow in Middle-Aged Adults at Risk for Alzheimer’s Disease: A Pilot Study
Carlsson CM, Xu G, Wen Z,  Barnet JH, Blazel HM, Chappell RJ, Stein JH, Asthana S, Sager MA, Alsop DC, Rowley HA, Fain SB and Johnson SC
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00100]

Background/Aims: Hypercholesterolemia in midlife increases risk for Alzheimer’s disease (AD) and contributes to cerebrovascular dysregulation - an early finding in preclinical AD pathology. Statins improve vascular reactivity, but it is unknown if they increase regional cerebral blood flow (CBF) in individuals at risk for AD.

Methods: In a randomized, controlled, double-blind pilot study, 16 asymptomatic middle-aged adults with parental history of AD were randomized to atorvastatin or placebo daily for 4 months. At baseline and month 4, regional CBF was measured using arterial spin-labeling magnetic resonance imaging and endothelial function was measured using brachial artery ultrasound.

Results: At baseline, participants with low HDL-cholesterol, higher global vascular risk, and greater endothelial dysfunction had reduced regional CBF in areas of the brain related to memory and learning (all p<0.03). Using voxel-based analysis, 4 months of atorvastatin increased CBF in bilateral hippocampi, fusiform gyrus, putamen and insular cortices compared to placebo.

Conclusion: In this pilot study, atorvastatin increased regional CBF in persons at risk for AD. Further research is warranted to confirm whether statins increase CBF in areas of the brain related to memory and learning and whether such perfusion changes are associated with a delay in the onset of AD.
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Measuring Alzheimer disease progression with transition probabilities: Estimates from NACC-UDS
Spackman DE, Kadiyala S, Neumann PJ, Veenstra DL and Sullivan SD
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00101]

Objectives: Estimate the probabilities, for Alzheimer's disease (AD) patients, of transitioning between stages of disease severity (mild, moderate, severe, dead) and care settings (community, institutional).

Methods: Data were compiled by the National Alzheimer Coordinating Center. The main analyses were limited to 3,852 patients who were >50 years old, diagnosed with possible/probable AD and had at least two center visits. A multinomial logistic model accounting for patient and center level correlation was used to calculate transition probabilities between stages of the Clinical Dementia Rating (CDR). Separately we calculated the probabilities of being institutionalized based on CDR stage. Both analyses controlled for baseline age, time between visits, sex, marital status, whether white, whether Hispanic and number of years of education.

Results: The annual probabilities of dying for patients in mild, moderate and severe health states were 5.5%, 21.5% and 48.0%, respectively, while the annual probabilities for institutionalization were 1.2%, 3.4% and 6.6%, respectively. The majority of mild and moderate patients remain in the same health state after one year, 77.4% and 50.1% respectively. Progressing patients are most likely to transition one stage, but 1.3% of mild patients become severe in one year. Some patients revert to lower severity stages, 7% from moderate to mild.

Conclusions: Transition probabilities to higher CDR stages and to institutionalization are lower than those published previously, but the probability of death is higher. These results are useful for understanding AD progression and can be used in simulation models to evaluate costs and compare new treatments or policies.


Ginsenoside Rg1 attenuates oligomeric Aβ_1-42-induced mitochondrial dysfunction 
Huang T, Fang F, Chen L, Zhu Y, Zhang J, Chen X and Yan SS
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00102]

Mitochondrial dysfunction is one of the major pathological changes seen in Alzheimer’s disease (AD). Amyloid beta-peptide (Aβ), a neurotoxic peptide, accumulates in the brain of AD subjects and mediates mitochondrial and neuronal stress. Therefore, protecting mitochondrion from Aβ-induced toxicity holds potential benefits for halting and treating and perhaps preventing AD. Here, we report that administration of ginsenoside Rg1, a known neuroprotective drug, to primary cultured cortical neurons, rescues Aβ-mediated mitochondrial dysfunction as shown by increases in mitochondrial membrane potential, ATP levels, activity of cytochrome c oxidase (a key enzyme associated with mitochondrial respiratory function), and decreases in cytochrome c release. The protective effects of Rg1 on mitochondrial dysfunction correlate to neuronal injury in the presence of Aβ. This finding suggests that ginsenoside Rg1 may attenuate Aβ-induced neuronal death through the suppression of intracellular mitochondrial oxidative stress and may rescue neurons in AD.
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PSEN1 Promoter Demethylation in Hyperhomocysteinemic TgCRND8 Mice is the Culprit,
not the Consequence
Fuso A, Cavallaro RA, Nicolia V and Scarpa S
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00103]

In recent years, in parallel with the growing awareness of the multifactorial nature of Late Onset
Alzheimer’s Disease, the possibility that epigenetic mechanisms could be involved in the onset
and/or progression of the pathology assumed an increasingly intriguing and leading role in
Alzheimer’s research. Today, many scientific reports indicate the existence of an epigenetic drift
during ageing, in particular in Alzheimer’s subjects. At the same time, experimental evidences are provided with the aim to demonstrate the causative or consequential role of epigenetic mechanisms. Our research group was involved in the last ten years in studying DNA methylation, the main epigenetic modification, in relationship to altered one-carbon metabolism (namely high homocysteine and low B vitamins levels), in Alzheimer’s experimental models. Our previous findings about the demethylation of Presenilin1 gene promoter in nutritionally-induced
hyperhomocysteinemia in a transgenic mouse model clearly demonstrated that Presenilin1 is regulated by DNA methylation. One of the open questions raised by our studies was if the observed demethylation was solely due to the induced imbalance of one-carbon metabolism or could be a response to the massive deposition of amyloid plaques in transgenic mice. Here we analyzed old (10 months) mice under standard diet in order to evidence possible changes in Presenilin1 promoter methylation in transgenic (TgCRND8 mice, carrying a double-mutated human APP transgene) vs. wt mice (129Sv) after prolonged exposure to amyloid. We found no differences in Presenilin1 methylation despite a slight increase in gene expression; these results suggest that amyloid production is not responsible for Presenilin1 demethylation in TgCRND8 mice brain.
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Age-related increase in levels of 5-hydroxymethylcytosine in mouse hippocampus is prevented by caloric restriction
Chouliaras L, van den Hove DLA, Kenis G, Keitel S, Hof PR, van Os J, Steinbusch HWM, Schmitz C and Rutten BPF
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00104]

Aberrations in epigenetic marks have been associated with aging of the brain while caloric restriction (CR) and upregulation of endogenous antioxidants have been suggested as tools to attenuate the aging process. We have recently observed age-related increases in levels of 5-methylcytidine (5-mC) and DNA methyltransferase 3a (Dnmt3a) in the mouse hippocampus. Most of those age-related changes in these epigenetically relevant markers were prevented by CR but not by transgenic overexpression of the endogenous antioxidant superoxide dismutase 1 (SOD1). As recent work has suggested a distinct role for hydroxymethylation in epigenetic regulation of gene expression in the brain, the current study investigated age-related changes of 5-hydroxymethylcytosine (5-hmC) in the mouse hippocampus, and furthermore tested whether CR and transgenic upregulation of SOD1 affected any age-related changes in 5-hmC. Immunohistochemical analyses of 5-hmC in 12- and 24-month-old wild-type and transgenic mice overexpressing SOD1, which were kept under either a control or a calorie restricted diet, revealed an increase of 5-hmC immunoreactivity occurring with aging in the hippocampal dentate gyrus, CA3 and CA1-2 regions. Moreover, CR, but not overexpression of SOD1, prevented the age-related increase in the CA3 region. These findings indicate that the aging process in mice is connected with profound changes in the epigenetic machinery in the hippocampus. Whether the observed epigenetic patterns associated with CR mediate the beneficial effects of CR on the life-span remains to be elucidated.
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The role of 5-hydroxymethylcytosine in aging and Alzheimer’s disease: current status and prospects for future studies
van den Hove DLA, Chouliaras L and Rutten BPF
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00105]

Epigenetic modifications have been proposed to underlie age-related dysfunction and age-related disorders. 5-hydroxymethylcytosine (5-hmC) is a newly described epigenetic modification. It is generated by the oxidation of 5-methylcytosine (5-mC) by the ten-eleven translocation (TET) family of enzymes. Various studies have shown that 5-hmC is present in high levels in the brain. Its lower affinity to methyl-binding proteins as compared to 5-mC suggests that it might have a different role in the regulation of gene expression, while it is also implicated in the DNA demethylation process. Interestingly, various widely used methods for DNA methylation detection fail to discriminate between 5-hmC and 5-mC, while numerous specific techniques are currently being developed. Recent studies have indicated an increase of 5-hmC with age in the mouse brain as well as an age- and gene-expression-level–related enrichment of 5-hmC in genes implicated in neurodegeneration. These findings suggest that 5-hmC may play an important role in the etiology and course of age-related neurodegenerative disorders. The present perspective summarizes the current knowledge on 5-hmC, discusses methodological challenges related to its detection, and suggests future strategies for examining the functional role of this epigenetic modification and its possible implication in aging and Alzheimer’s disease.
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DNMT3B promoter polymorphisms and risk of late onset Alzheimer’s disease
Coppedè F, Zitarosa MT, Migheli F, Lo Gerfo A, Bagnoli S, Dardano A, Nacmias B, Mancuso M, Monzani F, Siciliano G, Sorbi S and Migliore L
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00106]

The vast majority of Alzheimer’s disease (AD) are late-onset forms (LOAD) likely due
to the contribution of genetic, environmental, and stochastic factors, superimposed on a physiologically age-related decline of neuronal functions. Increasing evidence indicates epigenetic modifications in LOAD brains, and many of the environmental factors associated with AD risk, such as heavy metals and dietary factors, are able to modify the epigenome. There is also indication that environmentally-induced early life modifications of the genome during embryogenesis and brain development could contribute to the development of the disease later in life. DNA methyltransferase 3b (DNMT3b) is an enzyme involved in de novo methylation of the epigenome during embryogenesis, expressed in progenitor cells during neurogenesis. In the present study we evaluated two functional DNMT3B promoter polymorphisms, namely -149 C>T (rs2424913) and - 579 G>T (rs1569686), as candidate LOAD risk factors. Our analysis of 376 Italian LOAD patients and 308 matched controls revealed no difference in allele frequencies between the case an the control group (OR = 1.10 (0.88-1.39) for rs2424913, and OR = 1.02 (0.81-1.28) for rs1569686). Also the genotype distributions of both polymorphisms were closely similar between groups, and no significant effect on disease age at onset was observed. Overall, present results do not support a major role for rs2424913 or rs1569686 in LOAD pathogenesis.
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Alzheimer’s Disease and Environmental Exposure to Lead: The Epidemiologic Evidence and Potential Role of Epigenetics
Bakulski KM, Rozek LS, Dolinoy DC, Paulson HL and Hu H
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00107]

Several lines of evidence indicate that the etiology of late-onset Alzheimer’s disease (LOAD) is complex, with significant contributions from both genes and environmental factors. Recent research suggests the importance of epigenetic mechanisms in defining the relationship between environmental exposures and LOAD. In epidemiologic studies of adults, cumulative lifetime lead (Pb) exposure has been associated with accelerated declines in cognition. In addition, research in animal models suggests a causal association between Pb exposure during early life, epigenetics, and LOAD. There are multiple challenges to human epidemiologic research evaluating the relationship between epigenetics, LOAD, and Pb exposure. Epidemiologic studies are not well-suited to accommodate the long latency period between exposures during early life and onset of Alzheimer’s disease. There is also a lack of validated circulating epigenetics biomarkers and retrospective biomarkers of Pb exposure. Members of our research group have shown bone Pb is an accurate measurement of historical Pb exposure in adults, offering an avenue for future epidemiologic studies. However, this would not address the risk of LOAD attributable to early-life Pb exposures. Future studies that use a cohort design to measure both Pb exposure and validated epigenetic biomarkers of LOAD will be useful to clarify this important relationship.
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Alzheimer’s disease biomarkers and epigenetic intermediates following exposure to
Pb in vitro
Bihaqi SW and Zawia NH
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00108]

Late onset Alzheimer’s disease (LOAD) is typical of the majority of Alzheimer’s disease (AD) cases (~90%), and has no clear genetic association. Previous studies from our lab suggest that an epigenetic component could be involved. Developmental exposure of primates and rodents to lead (Pb) predetermined the expression of AD-related genes, such as the amyloid-β precursor protein (AβPP), later in life. In addition to AβPP, the preponderance of genes that were reprogrammed were rich in CpG dinucleotides implicating DNA methylation and chromatin restructuring in their regulation. To examine the involvement of epigenetic intermediates in Pb-induced alterations in gene expression, differentiated SH-SY5Y cells were exposed to a series of Pb concentrations (5-100 μM) for 48 h and were analyzed for the protein expression of AβPP, β-site amyloid precursor protein cleaving enzyme 1 (BACE1), specificity protein 1 and 3 (Sp1, Sp3) and epigenetic intermediates like DNA methyltransferase 1, 3a (Dnmt1, Dnmt3a) and methyl CpG binding protein 2 (MeCP2) involved in DNA methylation, six days after the exposure had ceased.. Western blot analysis indicated a significant latent elevation in AD biomarkers as well as the transcription factors Sp1 and Sp3, accompanied by a significant reduction in the protein levels of DNA methylating enzymes. RT-PCR analysis of Dnmt1, Dnmt3a and MeCP2 indicated a significant down-regulation of the mRNA levels. These data suggest that Pb interferes with DNA methylating capacity in these cells, thus altering the expression of AD-related genes.
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Lys²⁰³ and Lys³⁸² are essential for the proteasomal degradation of BACE1
Wang R, Ying Z, Zhao J, Zhang Y, Wang R, Lu H, Deng Y, Song W and Qing H
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00109]

Amyloid β protein (Aβ) is the primary component of senile plaques in Alzheimer’s disease brains and its aggregate form is neurotoxic. Aβ is generated through proteolysis of β-amyloid precursor protein (APP) by two proteases: γ-secretase and Chakravarti-secretase. BACE1, the β-secretase in vivo and the key rate-limiting enzyme that initiates the formation of Aβ, is an attractive drug target for AD therapy. Our previous study demonstrated that BACE1 is ubiquitinated and its degradation and effect on APP cleaving process are mediated by the ubiquitin-proteasome pathway. However, the specific underlying mechanism is still not well defined. In present study, we determined the specific binding sites responsible for the proteasomal degradation of BACE1. Ten fragments of human BACE1 cDNA with each of them containing 1 to 3 Lys codons were cloned, and HEK293 cells transfected with these recombinant plasmids were treated with specific proteasome inhibitor lactacystin. The protein levels of fragment-3 (Pro¹⁴⁹-Leu¹⁸⁰), -4 (IIe¹⁷⁹-Ser²³⁰) and -8 (Met³⁴⁹-Arg⁴⁰⁰) were significantly increased by lactacystin treatment, and immunocytochemical staining results showed that fragment-3, -4 and -8 proteins were colocalized with ubiquitin. Site-directed mutagenesis at Lys²⁰³ and Lys³⁸² of BACE1 abolished the proteasomal degradation of BACE1 and affected APP processing at β site and Aβ production. Taken together, our study demonstrated that BACE1 Lys²⁰³ and Lys³⁸² are essential for its proteasomal degradation, and the results may advance our understanding of regulation of BACE1 and APP processing by the ubiquitin proteasome system in AD pathogenesis and shed new insights on its pharmaceutical potential.
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The Role of TMP21 in Trafficking and Amyloid-β Precursor Protein (APP) Processing in Alzheimer’s Disease
Bromley-Brits K and Song W
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00110]

Alzheimer’s Disease (AD) is the most common neurodegenerative disorder leading to dementia. A major neuropathological hallmark of AD is the deposition of amyloid-β protein (Aβ) in the form of neuritic plaques. Aβ is formed by the sequential cleavage of amyloid-β precursor protein (APP) by β- and γ-secretase. It was recently suggested that TMP21 is a novel member of the γ-secretase complex which negatively regulates APP cleavage at the γ-site, but does not affect cleavage of APP or Notch at the ε-site . In vitro knockdown of TMP21 increases Aβ production and AD patients have less TMP21 expressed in their brains, suggesting that a deficiency in TMP21 may exacerbate AD pathology. TMP21 is most commonly known for its role in vesicle trafficking. Here we present the most recent research on TMP21 in relation to AD, including TMP21’s roles in the modulation of γ-secretase activity and protein trafficking.
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Editorial: RIPpers at the Membrane – A brief history of APP Secretases, their Substraes and their Functions
Hartmann D
[BSP/CAR/E-Pub/00111]

During the past 12 years, generation of intracellular signals by regulated cleavage of membrane proteins has made its way from a newcomer on the scientific stage (introduced by a battery of key papers appearing between 1998 and 2000, as reviewed in [1]), to a central signaling mechanism, termed Regulated Intramembrane Proteolysis (RIP), now presented in all standard textbooks of cell biology.


In retrospect, it is intriguing to see how during the roughly 10 years preceding this breakthrough quite diverse lines of research have laid down the foundation for both the concept itself as well as for the identification of the three APP secretases, which are now accepted as an important machinery for the RIPping of a growing list of functionally important proteins. This story is the more fascinating, as en route with the new signaling paradigm two likewise novel enzyme architectures, disintegrin proteases and i-CliPs, had to enter the scientific stage as well.

To start from the perspective of Alzheimers Disease, isolation of Aβ [2] and later APP provided the first example for the constitutive release of protein fragments from the membrane including the then almost unbelievable observation of proteolysis within the membrane plane [3, 4, reviewed in 5].  Further conceptual advances were made possible by the understanding of the SREBP signaling pathway, not only because it was the first one for which the two - step proteolysis scheme was elucidated as a signaling event, but also because it opened the road for the identification of enzymes similar to S2P and thus to RIP in eubacteria, documenting the phylogenetic age and conservation of such signaling techniques (reviewed in [1]).

Then – almost ironically – two of the severe familial forms of AD offered a crucial genetic approach to identify and analyze PSEN1 and later PSEN2 and thus the active core of γ-secretase. Specifically, knockout data demonstrated the essential role of PSENs in APP (and later Notch) γ-secretase cleavage, while inhibitor data pointed towards their intramembrane aspartyl protease activity. In parallel, mutagenesis approaches targeting two conserved aspartates at the same transmembrane level in neighbouring TMDs of PSENs confirmed that this unusual proteolytic center is indeed crucial for γ secretase activity. Together, these approaches opened the way to our current understanding of this entirely novel type of an intramembrane – acting enzyme [6, 7], subsequently augmented by the demonstration that PSENs can only act as members of  multiprotein complexes, whereby the composition of which would allow for the formation of different isocomplexes with – to some degree – different functional properties [8].

Along an independent line of research, pinpointing “the” APP secretase, now termed α-secretase, dependent on the identification of an entire novel class of enzymes, the disintegrin proteases of the ADAM family [9] during roughly the same time period. The first of these mammalian membrane-resident counterparts of snake venom disintegrin proteases were characterized for their role in sperm-egg interaction and only later revealed relatives acting as sheddases for now a multitude of membrane proteins (reviewed in [10}. Until 2000, at least three close candidates among the ADAM family had been proposed as α-secretase candidates, with a final decision for ADAM10 pending until the recent availability of a conditional knockout mouse.

Still within the same time window, a more conventional aspartyl protease termed BACE1 or asp2 arrived on the scenery, independently and almost simultaneously identified by five groups (reviewed in [11]). Taken together, both the concepts of RIP as well as key data on the enzyme machinery responsible for intramembrane proteolysis were thus established around the year 2000.

What has happened since then ?

In terms of cell biology, the following years were characterized by a flurry of novel substrates especially for γ-secretase and the ADAM proteases, starting with the Notch receptor already in 1999 (e.g. ref [7], and overview in [8] as well as similar data obtained on the genetic level in nematodes and fruit flies [12, 13] . The substrate list then expanded into e.g. adhesion molecules, surface proteoglycans, immune regulators growth factors and their receptors, just to name a few. For PSENs, additional, non-enzymatic functions as catenin docking stations and ionophores followed. Thereby, the list of proven i-CliP substrates rapidly exceeded the list of identified intracellular signaling pathways, leading to the concept that i-CliPping might not only be employed as a signal liberator, but in many cases could merely act as an intramembrane proteasome to remove the transmembrane debris of functionally relevant shedding events [14].  It is especially striking thereby that many ADAM10 substrates subsequently turned out to be γ-secretase substrates and vice versa.

In terms of AD therapy, initial high hopes of inhibiting γ-secretase as the enzyme finally liberating Aβ had to be rapidly mitigated upon the demonstration of Notch cleavage and the associated disastrous knockout phenotypes in PSEN deficient organisms. Even partial long-term reduction of PSEN activity in a genetic model had severe consequences in terms of skin tumours, intestinal defects and severe autoimmune disease ([15], and references therein), indicating that even a small-scale activity reduction aimed at postponing the clinical manifestation of AD would require logistically demanding and expensive inhibitor dosage controls, rendering this approach less suitable and probably too expensive for the expected vast number of patients (see [16] for a recent overview of this topic). Likewise, the somewhat belated identification of critical knockout phenotypes and important substrates for BACE1 have somewhat reduced, but not abolished, its initial attractivity as a drug target [17 – 19], and the practical importance of these potential risks of BACE1 inhibition in a future therapy is now under investigation.  An alternative approach has recently been devised based upon experimental overexpression of ADAM10, which at least under experimental conditions was reasonably well tolerated in mice, probably due to fact that cleavage of several critical substrates like Notch receptors by ADAM10 requires regulatory signals like ligand binding. Still, for other substrates including APP a substantial constitutive cleavage has been described, and the (long-term) consequences of their increased processing may be significant (and adverse) as well [19].

With the current volume, we have assembled for all three secretases and their two most notorious substrates, APP and Notch receptors, a series of review papers, both to summarize the most important steps of their respective research history as well as to provide an overview on currently discussed aspects like enzyme regulation and novel functions. Specifically, contributions by Vincent and Checler as well as Endres and Fahrenholz in this volume will provide a detailed overview on α – secretase(s) and their substrates including therapeutic options, while the review by S. Lichtenthaler mainly focuses on recent advances in the regulation of cleavage by ADAMs. BACE1 / β - secretase is represented by two accounts by Huth and Alzheimer and Fleck et al., focusing on recently discovered BACE1 substrates, sodium channels and neuregulins, respectively. A detailed update on the long-standing question of APP signaling via its γ-secretase – derived AICD fragment is provided by U. Konietzko, while the role of APP and Aβ in neurons and their synapses is discussed in detail by Wang et al.. Finally, the second substrate ever discovered for the APP secretase RIPping  machinery, the Notch receptor, is presented by the account of Sato et al., focusing on its more recently discussed role in the postdevelopmental organism. With this content, this current Special Issue of Current Alzheimer Research continues and updates the work presented by a former volume of this series (see [20] for introduction.

References

[1] Brown MS, Ye J, Rawson RB, Goldstein JL. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100: 391-398 (2000).

[2] Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Nat Acad Sci 82: 4245-4249 (1985).

[3] Kang J, Lemaire H-G, Unterbeck A, Salbaum JM, Masters CL, Grzeschik K-H, et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325: 733-736 (1987).

[4] Tanzi RE, Gusella JF, Watkins PC, Bruns GAP, St. George-Hyslop P, Van Keuren ML, et al. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235: 880-884 (1987).

[5] Kopan R, Goate A. A common enzyme connects notch signaling and Alzheimer's disease. Genes Dev 2000 14: 2799-2806 (2000).

[6] Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398: 513-517 (1999).

[7} De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398: 518-522 (1999).

[8] De Strooper B, Annaert W. Novel research horizons for presenilins and γ-secretases in cell biology and disease. Annu Rev Cell Dev Biol 26: 235-260 (2010).

[9] Wolfsberg TG, Straight PD, Gerena RL, Huovila AP, Primakoff P, Myles DG, et al. ADAM, a widely distributed and developmentally regulated gene family encoding membrane proteins with a disintegrin and metalloprotease domain. Dev Biol 169: 378-383 (1995).

[10] Deuss M, Reiss K, Hartmann D. Part-time -secretases: the functional biology of ADAM 9, 10 and 17. Curr Alzheimer Res 5:187-201 (2008).

[11] Cole SL, Vassar R. The role of amyloid precursor protein processing by BACE1, the beta-secretase, in Alzheimer disease pathophysiology. J Biol Chem 283: 29621-29625 (2008).

[12] Li X, Greenwald I. HOP-1, a Caenorhabditis elegans presenilin, appears to be functionally redundant with SEL-12 presenilin and to facilitate LIN-12 and GLP-1 signaling. Proc Natl Acad Sci USA 94: 12204-9 (1997).

[13] Struhl G, Greenwald I. Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398: 522-5 (1999).

[14} Kopan R, Ilagan MX. Gamma-secretase: proteasome of the membrane? Nat Rev Mol Cell Biol 5: 499-504 (2004).

[15] Tournoy J, Bossuyt X, Snellinx A, Regent M, Garmyn M, Serneels L, et al. Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice. Hum Mol Genet 13: 1321-1331 (2004).

[16] Sambamurti K, Greig NH, Utsuki T, Barnwell EL, Sharma E, Mazell C, et al. Targets for AD treatment: conflicting messages from γ-secretase inhibitors. J Neurochem 117:359-374 (2011).
[17] Dominguez D, Tournoy J, Hartmann D, Huth T, Cryns K, Deforce S, et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem 280: 30797-30806 (2005).

[18] Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, et al. Control of peripheral nerve myelination by the beta-secretase BACE1. Science 314: 664-666 (2006).

[19} De Strooper B, Vassar R, Golde T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 6: 99-107 (2010).

[20] Checler F. Production and fate of amyloid peptides: recent advances and perspectives. Curr Alzheimer Res 5: 90-1 (2008).
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EPA and DHA differentially affect in vitro inflammatory cytokine release by peripheral blood mononuclear cells from Alzheimer’s patients
Serini S, Bizzarro A, Piccioni  E, Fasano E, Rossi C, Lauria A, Cittadini ARM, Masullo C and Calviello G
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00112]

It has been hypothesized that pro-inflammatory cytokines may play a pathogenic role in Alzheimer’s disease (AD), and that n-3 polyunsaturated fatty acids may be protective against the development and progression of this disease. A reduced release of inflammatory cytokines by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) from AD patients dietary supplemented with a mixture of eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) was recently reported. On this basis, we investigated the possible differential effects of the two purified fatty acids on inflammatory cytokine release, a subject still not explored, even though of great pharmacological interest. We treated in vitro phytohaemagglutinin (PHA)- or LPS-stimulated PBMCs from AD patients and age-matched healthy controls (HCs) with purified EPA or DHA. Higher pro- to anti-inflammatory cytokine ratios, indicative of a pro-inflammatory profile, were observed in PHA-stimulated PBMCs from AD patients in basal conditions. The addition of both EPA and DHA markedly reduced the cytokine release, with DHA showing always a more prominent effect than EPA. However, whereas DHA reduced only the high IL-1β/IL-10 ratio, EPA was able to reduce also the IL-6/IL-10 ratio. In stimulated PMBCs from HCs the reducing effect on cytokine release was not always observed, or observed at a lower degree. In conclusion, whereas DHA appeared more powerful in inhibiting each single inflammatory cytokine, the pro-inflammatory profile of the AD patients’ cells was better reverted by EPA to a profile more similar to that found in HCs. A combination of both the fatty acids, seems to be still the best solution.
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Dementia after Age 75: Survival in Different Severity Stages and Years of Life Lost
Rizzuto D, Bellocco R, Kivipelto M, Clerici F, Wimo A and Fratiglioni L
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00113]

Dementia is a known predictor of mortality, but little is known about disease duration. We therefore aimed to investigate the impact of dementia on survival by estimating years lived with the disease, in total and in different severity stages, and by comparing dementia to other major chronic disorders such as cancer and cardiovascular disease (CVD).

During a 7.4-year follow-up of the Kungsholmen project, 371 incident dementia cases of the 1,307 dementia-free persons, aged 75+ at baseline, were clinically diagnosed (DSM-III-R criteria). Diagnoses of cancer and CVD were obtained from the national Stockholm Inpatient Registry System, active since 1969. Disease duration, hazard ratio (HR), and potential years of life lost (PYLL) were derived from Kaplan–Meier survival estimation, the Cox model, and standard life-table analysis, respectively.

Dementia was a significant predictor of mortality (HR=1.7; 95% CI: 1.47–1.92) after adjustment for several covariates including comorbidity, accounting for 16% of all deaths. The mean (±SD) survival time after dementia diagnosis was 4.1 (±2.6) years, and more than 2 years were spent in moderate (14-month) and severe (12-month) stages. Women with dementia lived longer than men, as they survived longer in the severe stage (2.1 vs. 0.5 years among 75–84-year-old women compared to coetaneous men). The PYLL were 3.4 for dementia, 3.6 for CVD, and 4.4 for cancer.

We found a similar impact of dementia and CVD on survival, but following diagnosis, persons with dementia, and especially women, spent half of their remaining lives in the severe disabling stages of the disease.
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The role of ER stress-induced apoptosis in neurodegeneration
Stefani IC, Wright D, Polizzi KM and Kontoravdi C
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00114]

Post-mortem analyses of human brain tissue samples from patients suffering from neurodegenerative disorders have demonstrated dysfunction of the endoplasmic reticulum (ER). A common characteristic of the aforementioned disorders is the intracellular accumulation and aggregation of proteins due to genetic mutations or exogenous factors, leading to the activation of a stress mechanism known as the unfolded protein response (UPR). This mechanism aims to restore cellular homeostasis, however, if prolonged, can trigger pro-apoptotic signals, which are thought to contribute to neuronal cell death. The authors present evidence to support the role of ER stress-induced apoptosis in Alzheimer’s, Parkinson’s and Huntington’s diseases, and further examine the interplay between ER dyshomeostasis and mitochondrial dysfunction, and the function of reactive oxygen species and calcium ions (Ca²⁺) in the intricate relationship between the two organelles. Possible treatments for neurodegenerative diseases that are based on combating ER stress are finally presented.
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Computer Based Classification of MR Scans in First Time Applicant Alzheimer Patients
Fatma Polat F , Demirel SO, Kitis O, Simsek F, Haznedaroglu  DI, Coburn K, Kumral E and Gonul AS
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00115]

In this study, we aimed to classify MR images for recognizing Alzheimer Disease (AD) in a group of patients who were recently diagnosed by clinical history and neuropsychiatric exams by using non-biased machine-learning techniques. T1 weighted MRI scans of 31 patients with probable AD and 31 age- and gender-matched cognitively normal elderly were analyzed with voxel-based morphometry and classified by support vector machine (SVM), a machine learning technique. SVM could differentiate patients from controls with accuracy of 74 % (sensitivity: 70 % and specificity: 77 %) when the whole brain was included the analyses. The classification accuracy was increased to 79 % (sensitivity: 65 % and specificity: 93 %) when the analyses restricted to hippocampus. Our results showed that SVM is a promising tool for diagnosis of AD, but needed to be improved.
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PP2A and Alzheimer Disease
Torrent L and Ferrer I
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00116]

Phosphorylation and, therefore, binding capacity of microtubule-associated protein tau is regulated by specific kinases and phosphatases. Activation of tau kinases plays a crucial role in tau- hyper-phosphorylation in Alzheimer disease (AD) and related tauopathies. Among phosphatases, protein phosphatase 2A, PP2A, is a principal tau dephosphorylating enzyme in the brain. PP2A acts as trimer composed of a catalytic (PP2A C), a scaffolding (PP2A A) and a regulatory (PP2 AB; B55α) subunit. Several abnormalities of PP2A have been reported in AD, including decreased mRNA and protein levels of the PP2A C (not replicated by other studies); decreased protein levels of the PP2A A and B55α; reduced PP2A C methylation at Leu309 due to impaired function methyltransferase type IV; increased PP2A C phosphorylation at Tyr307; up-regulation of the PP2A inhibitors I1 and I2; and loss of enzymatic activity. These observations indicate that PP2A is a putative target of therapeutic intervention considering that enhancing PP2A activity would decrease tau hyper-phosphorylation in AD. In spite of these achievements further studies are needed to replicate the reported individual different alterations converging in PP2A in AD.
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Do epigenetic pathways initiate late onset Alzheimer disease (LOAD): towards a new paradigm
Bihaqi SW, Schumacher A, Maloney B, Lahiri DK and Zawia NH
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00117]

Late onset Alzheimer’s disease (LOAD) is a non-familial, progressive neurodegenerative disease and the most prominent form of dementia in the elderly. Accumulating evidence suggests that LOAD not only results from the combined effects of variation in a number of genes and environmental factors, but also from epigenetic abnormalities such as histone modifications or DNA methylation. In comparison to monogenic diseases, LOAD exhibits numerous anomalies that suggest an epigenetic component in disease etiology. Evidence against a monogenic course and for an epigenetic component include: 1) the dominance of sporadic cases over familial ones and the low estimated concordance rates for monozygotic twins; 2) gender specific susceptibility and course of disease; 3) parent–of–origin effects, and late age of onset; 4) brain chromatin abnormalities, non–Mendelian inheritance patterns, and atypical levels of folate and homocysteine; and 5) monoallelic expression patterns of susceptibility genes. The epigenome is particularly susceptible to deregulation during early embryonic and neonatal periods and thus disturbances during these periods can have latent lasting effects. The Latent Early-life Associated Regulation (LEARn) model attempts to explain these consequences from a brain specific point of view. In the present review we present the evidence that support the role of epigenetics in the development of AD and explore the potential pathways and mechanisms that may be involved.
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Applying Epigenetics to Alzheimer’s Disease via the Latent Early–life Associated Regulation (LEARn) Model
Maloney B, Sambamurti K,  Zawia N and Lahiri DK
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00118]

Alzheimer’s disease (AD) is a leading cause of senile dementia and has been extensively studied by several groups around the world. A general consensus, based on neuropathology, genetics and cellular and animal models, is that the 4 kDa amyloid β protein (Aβ) triggers a toxic cascade that induces microtubule–associated protein ι hyperphosphorylation and deposition. Together, these lesions lead to neuronal dysfunction modeled in animals and neurodegeneration that ultimately causes dementia. Genetic studies show that a simple duplication of the Aβ precursor (APP) with a 1.5–fold increase in expression, can cause dementia with the complete AD associated neuropathology. The most fully characterized form of AD is early onset familial AD (FAD). Unfortunately, by far the most common form of AD is late onset AD (LOAD). FAD has well–identified autosomally dominant genetic causes, absent in LOAD. It is reasonable to hypothesize that environmental influences play a much stronger role in etiology of LOAD than of FAD. It is further reasonable that the results of these environmental influences may mimic important aspects of FAD. Therefore, it is important to identify environmentally driven changes that “phenocopy” FAD. Epigenetic changes in expression are complex but stable determinants of many complex traits. Some aspects are regulated by prenatal and early post–natal development, others punctuate specific periods of maturation, and still others occur throughout life, mediating predictable changes that take place during various developmental stages. Environmental agents such as mercury, lead and, pesticides can disrupt the natural epigenetic program and lead to developmental deficits, mental retardation, feminization, and other complex syndromes. In this review we discuss latent early–life associated regulation (LEARn), where apparently temporary changes, induced by environmental agents, become latent and present themselves once again at maturity or senescence to increase production of Aβ that may cause AD. The model provides us with a novel direction for identifying potentially harmful agents that may induce neurodegeneration and dementia later in life and provides hope that we may be able to prevent age–related neurodegenerative disease by “detoxifying” our environment.
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Hippocampal Morphology and Autobiographic Memory in Mild Cognitive Impairment and Alzheimer’s Disease
Thomann PA, Seidl U, Brinkmann J, Hirjak D, Traeger T, Wolf RC, Essig M and Schröder J
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00119]

Autobiographical memory (AM) comprises memories of one’s own past that are characterized by a sense of subjective time and autonoetic awareness. AM deficits are among the major complaints of patients with Alzheimer’s disease (AD) even in early or preclinical stages. However, little is known on the association between cerebral alterations and AM in mild cognitive impairment (MCI) and AD. In the current study, patients with AD or MCI and healthy controls underwent high-resolution magnetic resonance imaging (MRI) and neuropsychological testing including semi-structured assessment of semantic and episodic AM of distinct lifetime periods. In MRI analysis, FSL-FIRST was used to automatically ascertain volume and shape of the hippocampal formation. Episodic, but not semantic AM loss was associated with morphological changes of the hippocampus, primarily involving the left hemisphere. According to shape analyses, these associations referred to regionally specific rather than global atrophy of the hippocampus. Our study demonstrates that loss of episodic AM early in the course of AD is associated with regionally confined hippocampal atrophy, thus supporting the multiple trace theory for the role of the hippocampus in episodic AM. Our findings are not only relevant for the understanding of memory function, but may also contribute to facilitating the early diagnosis of AD.
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Editorial: Epigenetics: A paradigm shift in understanding Alzheimer’s Disease
Zawia NH and Lahiri DK
[BSP/CAR/E-Pub/00120]

While the early onset form of “Familial” Alzheimer’s disease (FAD) has been shown to be a product of mutations in certain genes, the cause of late onset AD (LOAD) has remained an enigma. For a very long time, research on LOAD has been dominated by theories that ascribed the majority of disease etiology to dysfunctional proteins and has focused on the role of certain proteins involved in the amyloidogenic pathway or the formation of τ tangles. While this protein-centric approach to understanding LOAD is driven by the hallmark pathology seen in AD patients, to date, these endpoints and targets have failed to result in any disease-modifying therapeutic intervention, which, in any case, would be of limited use if administered in old age. The main reason for this is an inadequate knowledge of when and how AD pathogenesis begins. In this context, we present a special issue of the journal with eight selected articles with complementary themes that would help us to understand how epigenetics provide a holistic approach in understanding AD.

The best-supported approach to understanding changes in gene expression or cellular phenotypes that persist, or are retained, for the lifetime of a cell or organism is to invoke epigenetics, i. e., functionally relevant modifications to the genome that do not involve a change in the DNA sequence. A well-known example is the process of cellular differentiation and tissue specificity, in which various cells of the body specialize and perform varied functions, although they all contain the same underlying DNA sequence. It has been traditionally accepted that, once established in a post-mitotic cell, epigenetic modifications are highly stable and govern expression and tissue specificity by permanently shutting down certain genes and activating others. Therefore, in considering epigenetics as a potential mechanism that could contribute to AD pathogenesis late in life, the most conservative view would be to look only early in life to identify the perturbations to the gene expression program that may have occurred during brain development. This hypothesis could be supported by the findings reported in this special issue by Coppedè regarding DNMT3B promoter polymorphisms as a risk factor for AD [1]. Fundamental differences in DNA methylation could be due to such variations in DNA methylase gene regulation. Fuso provides a link between FAD and epigenetic hypotheses, identifying hypomethylation of the PSEN1 promoter in combined Swedish and Indiana transgenic mice as “the culprit, not the consequence” [2] However, these works do not only support the conservative hypothesis. DNM3TB regulatory variation can contribute just as easily to environmentally modulated methylome modification later in life, and PSEN1 hypomethylation can be a result of environmental stress, subject to environmental remediation [3-4].

Indeed, recent findings have shown that epigenetic modifications in the brain are dynamic. Neuronal activity and environmental influences has been shown to modulate the epigenetic landscape. DNA methylation also appears to be essential for long-term potentiation [5-7]. Bakulski and Hu herein review evidence linking exposure to lead (Pb) and its potential epigenetic role in AD [8]. Bihaqi and Zawia extend the Pb epidemiological model to specific in vitro systems [9]. However, DNA methylation may only tell part of the story. Variations in 5’-hydroxymethylcytosine (5’-hmc) levels, especially in brain, may play an important part in AD etiology. Van den Hove provides an overview of potential roles for 5’-hmc in AD and aging [10]. Chouliaris and Rutten look specifically at controlling age-related 5’-hmc changes by caloric restriction [11]. Therefore, in examining neurons in old age, we need to understand that their DNA can store within it both stable early developmental epigenetic modification as well as dynamic changes in the epigenetic landscape due to environmental exposure or physiological interactions over the lifetime of the individual.

In this Epigenetics and AD issue, which may be the first of its kind, we explore the connections between the roles of epigenetics, including environmental factors, on the etiology of the disease. In addition to studies using animal models, cell culture, and human tissue, we t discuss the relationship between epigenetic modification and their subsequent effect on processes known to be related to AD. The Developmental Origins of Health and Disease (DOHaD) hypothesis, previously known as the Fetal-basis of Adult Disease (FEBAD), posits that perturbations (external or internal) early in the life of an organism can affect pathophysiology in adulthood [12-13]. However, specific, testable molecular mechanisms were not explored in depth. Basha et al. provided the first evidence that early life exposure to an environmental toxin, Pb, enhanced the expression of AD-related biomarkers late in life [14]. That lifespan study in rodents, followed by later primate studies [15], provided the first clue for a developmental origin and an environmental link to AD and opened the door for the exploration of potential mechanisms. This was capitulated and broadened by the Latent Early-life Associated Regulation (LEARn) model to include other CNS disorders and perturbations [16-17]. LEARn proposes specific, testable molecular pathways, united as epigenetic mechanisms, particularly the envirome/exposome (cumulative profile of environmental effects on epigenetic markers), the DNA methylome, and the DNA oxidome (cumulative profile of oxidative modification to genomic and mitochondrial DNA) [18]. Bihaqi and Zawia provide in this issue a comprehensive review on epigenetic pathways as a new paradigm for understanding etiology [19]; and Maloney and Lahiri present the LEARn model as a specific, unifying and testable hypothesis linking environmental influence through epigenetic mechanisms leading to AD [20]. Finally, we sincerely thank all the authors for their great contributions, and the reviewers for their invaluable inputs.

References

[1] Coppedè F (2012) DNMT3B promoter polymorphisms and risk of late onset Alzheimer's disease. Current Alzheimer Research.
[2] Fuso A (2012) PSEN1 promoter demethylation in hyperhomocesteinemic TgCRND8 mice is the culprit, not the consequence. Current Alzheimer Research.
[3] Rogers EJ, Milhalik S, Orthiz D, Shea TB (2004) Apple juice prevents oxidative stress and impaired cognitive performance caused by genetic and dietary deficiencies in mice. J Nutr Health Aging 8, 92–97.
[4] Chan A, Shea TB (2006) Supplementation with apple juice attenuates presenilin-1 overexpression during dietary and genetically-induced oxidative stress. J Alzheimers Dis 10, 353–358.
[5] Levenson JM, Roth TL, Lubin FD, Miller CA, Huang IC, Desai P, Malone LM, Sweatt JD (2006) Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem 281, 15763-15773.
[6] Nelson ED, Kavalali ET, Monteggia LM (2008) Activity-dependent suppression of miniature neurotransmission through the regulation of DNA methylation. J Neurosci 28, 395-406.
[7] Iwamoto K, Bundo M, Ueda J, Oldham MC, Ukai W, Hashimoto E, Saito T, Geschwind DH, Kato T (2011) Neurons show distinctive DNA methylation profile and higher interindividual variations compared with non-neurons. Genome Res 21, 688-696.
[8] Bakulski KM, Hu H (2012) Alzheimer's disease and environmental exposure to lead: the epidemiological evidence and potential role of epigenetics. Current Alzheimer Research.
[9] Bihaqi SW, Zawia NH (2012) Alzheimer's disease: epigenetic intermediates and exposure to Pb in an in vitro model. Current Alzheimer Research.
[10] van den Hove DLA (2012) The role of 5-hydroxymethylcytoxine in aging and Alzheimer's disease: current status and prospect for future studies. Current Alzheimer Research.
[11] Chouliaris L, Rutten BPF (2012) Age-related increase in levels of 5-hydroxymethylcytosine in mouse hippocampus is prevented by caloric restriction. Current Alzheimer Research.
[12] Barker DJ, Osmond C (1986) Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1, 1077-1081.
[13] Swanson JM, Entringer S, Buss C, Wadhwa PD (2009) Developmental origins of health and disease: environmental exposures. Semin Reprod Med 27, 391-402.
[14] Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW, Lahiri DK, Zawia NH (2005) The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain. J Neurosci 25, 823–829.
[15] Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, Harry J, Rice DC, Maloney B, Chen D, Lahiri DK, Zawia NH (2008) Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. Journal of Neuroscience 28, 3–9.
[16] Lahiri DK, Maloney B, Basha MR, Ge YW, Zawia NH (2007) How and when environmental agents and dietary factors affect the course of Alzheimer's disease: the "LEARn" model (latent early-life associated regulation) may explain the triggering of AD. Current Alzheimer Research 4, 219–228.
[17] Lahiri DK, Maloney B, Zawia NH (2009) The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases. Molecular Psychiatry 14, 992–1003.
[18] Lahiri DK (2011) An integrated approach to genome studies. Science 331, 147.
[19] Bihaqi SW, Zawia NH (2012) Are epigenetic pathways responsible for the mediation of late onset Alzheimer's disease (LOAD)? Towards a new paradigm. Current Alzheimer Research.
[20] Maloney B, Lahiri DK (2012) Applying epigenetics to Alzheimer's disease via the latent early-life associated regulation (LEARn) model. Current Alzheimer Research.
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Adult Changes in Thought Study: Dementia is an Individually Varying Convergent Syndrome with Prevalent Clinically Silent Diseases that may be Modified by Some Commonly Used Therapeutics
Montine TJ, Sonnen JA, Montine KS, Crane PK and Larson EB
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00121]

The Adult Changes in Thought (ACT) study is a longitudinal population-based prospective cohort study of brain aging and incident dementia in the Seattle metropolitan area. Observational studies using autopsies from ACT indicate that dementia is a convergent syndrome that commonly derives from Alzheimer’s disease (AD), microvascular brain injury (μVBI), and Lewy body disease (LBD), and that these diseases have prevalent subclinical forms that also are commonly co-morbid. The existence of subclinical diseases highlights potential opportunities to intervene before the development of clinically apparent impairments. Our observations suggest that some such interventions already may exist to suppress processes of AD (statin therapy) or μVBI (treatment of hypertension). Reduced burden of LBD is associated with cigarette smoking; although smoking is not recommended as an intervention, these exposure data may provide clues to alternative neuroprotective mechanisms. Self reported anti-oxidant supplementation was without apparent effect in this cohort on indices of AD, μVBI, or LBD. Continued observational studies of brain aging will provide further insight into the convergent complexity of the dementia syndrome and its subclinical forms as well as highlight potential interventions that will require validation in clinical trials.
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Overview and Findings from the Religious Orders Study
Bennett DA, Schneider JA, Arvanitakis Z and Wilson RS
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00122]

The Religious Orders Study is a longitudinal clinical-pathologic cohort study of aging and Alzheimer’s disease (AD). In this manuscript, we summarize the study methods including the study design and describe the clinical evaluation, assessment of risk factors, collection of ante-mortem biological specimens, brain autopsy and collection of selected post-mortem data. The results: 1) review the relation of neuropathologic indices to clinical diagnoses and cognition proximate to death; 2) examine the relation of risk factors to clinical outcomes; 3) examine the relation of risk factors to measures of neuropathology; and 4) summarize additional study findings. We then discuss and contextualize the study findings.
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University of Kentucky Sanders-Brown Healthy Brain Aging Volunteers: Donor Characteristics, Procedures, and Neuropathology
Schmitt FA, Nelson PT, Abner E, Scheff S, Jicha GA, Smith C, Cooper G, Mendiondo M, Danner DD, Van Eldik LJ, Caban-Holt A, Lovell MA and Kryscio RJ
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00123]

Cognitively intact elderly research volunteers at the University of Kentucky have been recruited, followed longitudinally, and autopsied with extensive neuropathological evaluations since 1989. To date, the cohort has recruited 1,030 individuals with 552 participants being actively followed, 363 deceased, and 273 autopsied. An extensive database has been constructed with continuous updates that include textured clinical, neuropsychological, neuroimaging, and pathological information. The history, demographics, clinical observations, and pathological features of this research cohort are described. We also explain some of the evolving methodologies and the academic contributions that have been made due to this motivated group of older Kentuckians.
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A Population-Based Clinicopathological Study in the Oldest-Old: The 90+ Study
Corrada MM, Berlau DJ and Kawas CH
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00124]

Population-based longitudinal clinicopathological studies provide an ideal opportunity to study a variety of risk and protective factors in relation to pathology associated with dementia in individuals who are representative of the general population. The 90+ Study is a population-based study designed specifically to study aging and dementia as well as its neuropathological correlates in participants 90 years of age and older. We present demographic and pathological data on the first 104 participants to come to autopsy from the brain donation component of the study, The 90+ Autopsy Study. Cognitive diagnosis was assigned according to Diagnostic and Statistical Manual 4th edition criteria for dementia and neuropathological diagnoses were made according to the Consortium to Establish a Registry for Alzheimer’s Disease protocol. Dementia was present in 61% of autopsied participants, the majority of whom were diagnosed with Alzheimer’s disease (85%). Many different types of pathology typically associated with dementia were common in the oldest-old, and included neurofibrillary tangles, neuritic plaques, diffuse plaques, Lewy bodies, hippocampal sclerosis, and cerebral infarctions. Most types of pathology were more frequently found in participants suffering from dementia but there was extensive overlap in pathology among those with and without dementia. In addition, 22% of demented participants did not have sufficient pathology to account for their cognitive loss. Our results highlight the poor associations between these common pathological lesions and dementia in the oldest-old and the importance of considering many different types of pathology, possibly including some yet to be identified, in order to account for all dementias in the oldest-old.
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Neuropathological correlates of falling in the CC75C population-based sample of the older old
Richardson K, Hunter S, Dening T, Xuereb JH, Matthews FE, Brayne C and Fleming J
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00125]

Background: Previous imaging studies have suggested links between brain pathologies and factors that are associated with falls such as gait, balance and daily function. Possible neuropathological correlates of older people’s falls have been suggested based on brain imaging studies, but to date none have been examined in brain tissue.

Methods: Falls data collected from repeated surveys of a population-based cohort of individuals aged at least 75 years old at baseline were related to neuropathological data collected from post-mortem examination of the study’s associated brain donor collection (n=212).

Results: Amongst people without dementia, most cerebrovascular neuropathological features examined, particularly white matter pallor, microinfarcts and microscopic atherosclerosis, were increasingly common across the sub-groups categorised by no reports of falling, only one or at least two reports of falling. The overall burden of pathology was greater in those with dementia, but only microinfarcts showed a similar increase with respect to reported falling status.

Conclusions: Subclinical pathologies sharing a common vascular origin are associated with increased falling amongst people with no dementia, as are microinfarcts in those with dementia. Although further research is needed to address the mechanisms of falls and their neuropathological correlates, the findings from the current study would suggest that if cerebrovascular disease prevention reduces vascular neuropathology changes this may have direct benefits in reducing falls amongst older people with or without dementia.
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The Framingham Brain Donation Program: Neuropathology Along The Cognitive Continuum
Au R, Seshadri S, Knox K, Beiser A, Himali JJ, Cabral HJ, Auerbach S, Green RC, Wolf PA and McKee AC
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00126]

The Framingham Heart Study has enrolled 3 generations of participants, the Original cohort (Gen 1) enrolled in 1948, the Offspring cohort (Gen 2) enrolled in 1971 and the Third Generation enrolled in 2002. Participants have been undergoing prospective surveillance for incident stroke and dementia and embedded within this cohort is the voluntary Framingham Brain Donation Program that was begun in 1997. Participants who register to become brain donors have had one or more brain MR and cognitive test batteries administered. In addition, they undergo neurological evaluation as indicated, record review and post-mortem next-of-kin interview to determine the presence, type and extent of antemortem, clinical neurological diagnoses and to assign a retrospective Clinical Dementia Rating (CDR) Scale score. Between 1997 and 2009 there were 1806 deaths, 186 of which were among registered brain donors and of these 139 brains could be examined. 58% were deemed cognitively normal at death. We present results for 3 projects; the first was to examine the sensitivity and specificity of our clinical diagnosis against the gold standard of pathological AD in 59 persons who underwent detailed cognitive assessment in the two years prior to death; we observed a 77.3% sensitivity (2 persons with AD were diagnosed clinically as Lewy body dementia) and a 91.9% specificity. The second examined the correlation of regional Alzheimer-type pathology to cognitive status at death among 34 persons who were over the age of 75 and without any significant vascular or alternative neurodegenerative pathology and found that neurofibrillary tangle counts distinguished between persons who were controls, had mild cognitive impairment, mild or moderate dementia; tangles in dorsolateral frontal cortex best distinguished MCI and controls. The third project examined the extent and severity of vascular pathology, again in a larger sample of varying cognitive abilities and in a subsample of persons with either amnestic or non-amnestic MCI. We observed that an aggregate ischemic injury score was significantly higher in persons with a CDR score of 0.5 than in normal controls.
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The Honolulu-Asia Aging Study: Epidemiologic and Neuropathologic Research on Cognitive Impairment
Gelber RP, Launer LJ and White LR
[Abstract] [FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00127]

The Honolulu-Asia Aging Study (HAAS) is a longitudinal epidemiologic investigation of rates, risk factors, and neuropathologic abnormalities associated with cognitive decline and dementia in aged Japanese-American men. The project was established in 1991 and will be brought to closure in 2012. Age-specific rates of total dementia and the major specific types of dementia in HAAS participants are generally similar to those reported from other geographic, cultural, and ethnic populations. Risk factors for dementia in the HAAS include midlife hypertension and other factors previously shown to influence cardiovascular disease. The autopsy component of the project has yielded novel findings, the most illuminating of which is the demonstration of 5 important lesion types linked independently to cognitive impairment. While one of these – generalized atrophy – is strongly associated with both Alzheimer lesions and microinfarcts, it also occurs in the absence of these lesions and is independently correlated with dementia. Each lesion type is viewed as representing a distinct underlying pathogenic process. Their summed influences is an especially robust correlate of dementia in the months and years prior to death.
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Overview and Findings From the Rush Memory and Aging Project
Bennett DA, Schneider JA, Buchman AS, Barnes LL and Wilson RS
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00128]

The Memory and Aging Project is a longitudinal, epidemiologic clinical-pathologic cohort study of common chronic conditions of aging with an emphasis on decline in cognitive and motor function and risk of Alzheimer’s disease (AD). In this manuscript, we first summarize the study design and methods. Then, we present data on: 1) the relation of motor function to cognition, disability, and death; 2) the relation of risk factors to cognitive and motor outcomes, disability and death; 3) the relation of neuropathologic indices to cognitive outcomes; 4) the relation of risk factors to neuropathologic indices; and 5) additional study findings. The findings are discussed and contextualized.
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The Minority Aging Research Study: Ongoing Efforts to Obtain Brain Donation in African Americans without Dementia
Barnes LL, Shah RC, Aggarwal NT, Bennett DA and Schneider JA
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00129]

The Minority Aging Research Study (MARS) is a longitudinal, epidemiologic cohort study of decline in cognitive function and risk of Alzheimer’s disease (AD) in older African Americans, with brain donation after death added as an optional component for those willing to consider organ donation. In this manuscript, we first summarize the study design and methods of MARS. We then provide details of ongoing efforts to achieve neuropathologic data on over 100 African Americans participating in MARS and in three other clinical-pathologic cohort studies at Rush University Medical Center. The results examine strategies for recruiting and consenting African Americans without dementia; 2) efforts to maintain high rates of follow-up participation; 3) strategies for achieving high rates of agreement to brain donation; and 4) the methodology of obtaining rapid brain autopsy at death. The implications of these efforts are discussed.
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The Nun Study: Risk Factors for Pathology and Clinical-pathologic Correlations
Morimer JA
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00130]

The Nun Study was the first cohort study to enroll and follow a large, well-defined population that included demented and non-demented participants, all of whom agreed to donate their brains for research. The inclusion of systematic neuropathologic analysis in this study has resulted in a greater understanding of the role of Alzheimer and vascular pathology in the expression of memory deficits and dementia and has provided data showing that biomarkers for the pathology may be evident many decades earlier in adult life.

Findings related to neuropathology in this study have included the following: (1) Although clinical outcomes were strongly correlated with Alzheimer neuropathology, about one-third of the participants fulfilling criteria for neuropathologic Alzheimer’s disease (AD) were not demented at the time of death. (2) Brain infarcts by themselves had little effect on cognitive status, but played an important role in increasing the risk of dementia associated with Alzheimer pathology. (3) Hippocampal volume was strongly correlated with Braak neurofibrillary stage even in participants with normal cognitive function. (4) A linguistic characteristic of essays written in early adult life, idea density, had a strong association with not only clinical outcomes in late life, but the severity of Alzheimer neuropathology as well. (5) The effect of apolipoprotein E-4 on dementia was mediated through Alzheimer, but not vascular pathology.
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The Neuropathology of Vascular Disease in the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS)
Richardson K, Stephan BCM, Ince PG, Brayne C, Matthews FE and Esiri MM
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00131]

Background: Vascular disease is associated with increased risk of dementia. Vascular health worsens with age. We investigated the relationship between self-reported vascular disease and brain pathology.

Methods: Brain donations to the population-based MRC Cognitive Function and Ageing Study (n=456, age range 66-103 years) were assessed using a standard protocol for Alzheimer’s Disease (AD) and cerebrovascular pathology. History of stroke, angina, diabetes, medicated hypertension and heart attack were identified from self- and proxy-report interviews, retrospective informant interviews and death certificates. Logistic regression was used to estimate associations between each health condition and dichotomised neuropathological variables adjusted for age and sex.

Results: Stroke (36%), angina (23%), diabetes (12%), medicated hypertension (35%) and heart attack (22%) were frequently reported. Self-reported stroke was strongly associated with vascular, but not AD pathology. Medicated hypertension was associated with increased microinfarcts (OR=2.1, 95%CI=1.3-3.7) and less severe neocortical tangles (OR=0.5, 95%CI=0.3-0.8) and cerebral amyloid angiopathy (OR=0.5, 95%CI=0.3-0.8). Heart attack was associated with increased microinfarcts (OR=2.1, 95%CI=1.2-3.9).

Conclusions: Vascular risk factors were not associated with an increased burden of AD pathology at death in old age. A positive association between indices of systemic cardiovascular health (treated hypertension and ischaemic heart disease) and cerebral microinfarcts emerged. The findings support the view that cerebral small vessel disease and cardiovascular disease are inter-related. Microinfarcts are emerging as an important correlate of age-related vascular cognitive impairment and the findings add weight to the argument for strategies to improve general cardiovascular health as a potential preventative strategy against cognitive decline in later life.
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Analysis of Copy Number Variation in Alzheimer's Disease: the NIA-LOAD/NCRAD Family Study
Swaminathan S, Shen L, Kim S, Inlow M, West JD, Faber KM, Foroud T, Mayeux R and Saykin AJ
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00132]

Copy number variants (CNVs) are DNA regions that have gains (duplications) or losses (deletions) of genetic material. CNVs may encompass a single gene or multiple genes and can affect their function. They are hypothesized to play an important role in certain diseases. We previously examined the role of CNVs in late-onset Alzheimer's disease (AD) and mild cognitive impairment (MCI) using participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study and identified gene regions overlapped by CNVs only in cases (AD and/or MCI) but not in controls. Using a similar approach as ADNI, we investigated the role of CNVs using 794 AD and 196 neurologically evaluated control non-Hispanic Caucasian NIA-LOAD/NCRAD Family Study participants with DNA derived from blood/brain tissue. The controls had no family history of AD and were unrelated to AD participants. CNV calls were generated and analyzed after detailed quality review. 711 AD cases and 171 controls who passed all quality thresholds were included in case/control association analyses, focusing on candidate gene and genome-wide approaches. We identified genes overlapped by CNV calls only in AD cases but not controls. A trend for lower CNV call rate was observed for deletions as well as duplications in cases compared to controls. Gene-based association analyses confirmed previous findings in the ADNI study (ATXN1, HLA-DPB1, RELN, DOPEY2, GSTT1, CHRFAM7A, ERBB4, NRXN1) and identified a new gene (IMMP2L) that may play a role in AD susceptibility. Replication in independent samples as well as further analyses of these gene regions is warranted.
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Pretreatment with memantine prevents Alzheimer-like alterations induced
by intrahippocampal okadaic acid administration in rats
Zimmer ER, Kalinine E, Haas CB, Torrez VR, Souza DO, Muller AP and Portela LV
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00133]

Cerebral okadaic acid (OA) administration induces Alzheimer’s disease (AD)- like phenotype in rats. Alterations in glutamate levels associated with hyperactivation of cyclin dependent kinase 5 (Cdk5) signaling pathway downstream Tau phosphorylation may participate in the genesis of this pathological phenotype. Here, we examined the efficacy of MN pretreatment on reducing OA-induced AD-like phenotypes in rats. Wistar rats were given daily intraperitoneal injections of MN for 3 days and then given an intrahippocampal infusion of OA. Animals were divided into four groups: control (CO), MN, OA and MN/OA. Spontaneous locomotion and spatial memory performance were assessed by open field and Morris water maze respectively. Additionally, we measured glutamate levels in the cerebrospinal fluid (CSF) and the immunocontent of Cdk5, p35, p25 and phosphorylated Tau (pTauSer199/202) in the hippocampus. Spontaneous locomotion did not differ between groups. The OA group showed a significant decrease in spatial memory performance compared to all groups. The OA infusion also increased CSF glutamate levels and the immunocontents of Cdk5, p25 and pTauSer199/202 in the hippocampus. Conversely, pretreatment with MN prevented OA-induced spatial memory deficits and the increment of CSF glutamate level; which paralleled with normal immunocontents of Cdk5, p25 and pTauSer199/202 proteins. There were positive correlations between spatial memory performance and the neurochemical parameters. In summary, pretreatment with MN prevents spatial memory deficits induced by intrahippocampal OA administration in rats. The prevention of increase CSF glutamate levels, along with the reduced hippocampal phosphorylation of TauSer199/202 by Cdk5/p25 signaling pathway, are the 3 mechanisms proposed to participate in the prophylactic effects of MN in this AD-like model.
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Chronic infusion of amyloid-β peptide and sustained attention altered α 7 nicotinic receptor density in the rat brain
Viel TA, Caetano AL, Albuquerque MS, Araujo MS and Buck  HS
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00134]

It is already known that progressive degeneration of cholinergic neurons in brain areas such as the hippocampus and the cortex leads to memory deficits, as observed in Alzheimer’s disease. This work verified the effects of the infusion of amyloid-β (Aβ) peptide associated to an attentional rehearsal on the density of α7 nicotinic cholinergic receptor (nAChR) in the brain of male Wistar rats. Animals received intracerebroventricular infusion of Aβ or vehicle (control – C) and their attention was stimulated weekly (Stimulated Aβ group: S-Aβ and Stimulated Control group: SC) or not (Non-Stimulated Aβ group: N-SAβ and Non-Stimulated Control group: N-SC), using an active avoidance apparatus. Conditioned avoidance responses (CAR) were registered. Chronic infusion of Aβ caused a 37% reduction in CAR for N-SAβ.  In S-Aβ this reduction was not observed. At the end, brains were extracted and autoradiography for α7 nAChR was conducted using [125I]-α-bungarotoxin. There was an increase in α7 density in hippocampus, cortex and amygdala of SAβ animals, together with the memory preservation. In recent findings from our lab using mice infused with Aβ and theα7 antagonist methyllycaconitine, and stimulated weekly in the same apparatus, it was observed that memory maintenance was abolished. So, the increase in α7 density in brain areas related to memory might be related to a participation of this receptor in the long-lasting change in synaptic plasticity, which is important to improve and maintain memory consolidation.
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Multi-target inhibitors for proteins associated with Alzheimer: In silico discovery using fragment-based descriptors
Speck-Planche A, Kleandrova VV , Luan F, Natália M and Cordeiro DS
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00135]

Alzheimer disease (AD) is one of the most common and serious neurodegenerative disorders in humans. For this reason, the search for new anti-AD chemotherapies is a very active area. Only few biological receptors associated with AD have been well studied. The efficacy of the current drugs is limited by the fact that they inhibit only one target like protein. Thus, the rational design of new drug candidates as versatile inhibitors for different proteins associated with AD constitutes a major goal. With the aim to overcome this problem, we developed here the first fragment-based approach by exploring quantitativestructure- activity relationships (QSAR). The principal purpose here, was the in silico design of multitarget (mt) inhibitors against five proteins associated with AD. Our approach was focused on the construction of an mt-QSAR discriminant model using a large and heterogeneous database of compounds and substructural descriptors, which permitted the simultaneous classification and prediction of inhibitors against five proteins associated with AD. The model correctly classified more than 90% of active and inactive compounds in both, training and prediction series. As principal advantage, this mt-QSAR discriminant model was used for the automatic and fast extraction of fragments responsible for the inhibitory activity against the five proteins under study, and new molecular entities were suggested as possible versatile inhibitors for these proteins.
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Magnetic resonance imaging in Alzheimer’s disease: from diagnosis to monitoring treatment effect
Filippi M, Agosta F, Frisoni GB, De Stefano N, Bizzi A, Bozzali M, Falini A, Rocca MA, Sorbi S, Caltagirone C and Tedeschi G
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00136]

Quantitative outcome variables in Alzheimer’s disease (AD) are of interest because of their low longitudinal variability compared with that of repeated clinical and cognitive measurements. Conventional MR-based volumetry of structures within and beyond the medial temporal lobe has proven to be useful in the diagnostic work up of early AD patients, and measures of atrophy have the potential to monitor the efficacy of disease-modifying agents. The extensive application of new non-conventional MR-based techniques to the study of AD, such as proton magnetic resonance spectroscopic imaging, diffusion tensor MRI, and functional MRI, has undoubtedly improved our understanding of the pathophysiology of the disease, and might lead to the identification of additional useful markers of disease progression. This review summarizes the main results obtained from the application of conventional and non-conventional MRI in AD patients, and supports their more extensive use in studies of disease evolution and clinical trials.
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The Effects of Cognitive Speed of Processing Training among Older Adults with Psychometrically- Defined Mild Cognitive Impairment
Valdés EG, O’Connor ML and Edwards JD
[FULL-TEXT INQUIRY] [BSP/CAR/E-Pub/00137]

Despite the growing interest in cognitive training programs as a potential non-pharmacological approach to slowing cognitive decline in mild cognitive impairment (MCI), there has been little research on the differential effectiveness of training among subtypes of MCI (i.e., amnestic, single non-amnestic, and multi-domain). The current study examined the longitudinal effects of cognitive speed of processing training (SOPT) among older adults with psychometrically-defined MCI from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial. Mixed model ANOVAs examined the effectiveness of SOPT in participants with MCI relative to controls and also compared training effectiveness in MCI subgroups to appropriate controls. A mixed effects model compared SOPT training effects longitudinally across five years relative to controls. A second mixed effects model compared the durability of training gains between the MCI subtypes across 5 years. All subtypes of MCI showed immediate improvement post-training relative to controls, with the single non-amnestic subtype showing the most benefit. Additionally, all subtypes showed similar trajectories across five years,. There were no significant changes in performance across time, indicating initial training gains were maintained. These results provide support for the effectiveness and potential durability of SOPT among persons with MCI regardless of subtype. Future research should investigate if SOPT transfers to improvements in the everyday functioning of those with MCI.
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