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OPEN ACCESS PLUS
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Contents
10(1): Pp. 4 - 10
Sean A. Pintchovski, Dale B. Schenk and Guriqbal S. Basi
[Open Access Plus] |
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The γ-secretase complex cleaves the carboxy-terminal 99 residue (C99) fragment of the amyloid precursor protein (APP) to generate the amyloid-β (Aβ) peptide. The catalytic activity of this complex is mediated either by the presenilin- 1 (PS1) or the presenilin-2 (PS2) subunit. In vitro and in vivo studies have demonstrated that PS1-containing complexes generate more total Aβ product than PS2-containing complexes, indicating greater cleavage activity by PS1- containing γ-secretase complexes at the APP γ-site. However, it remains untested whether γ-secretase cleavage at the APP ε-site, which precedes γ-site cleavage and produces the physiologically active APP intracellular domain (AICD), follows the same rule. Using a novel Swedish APP-GVP substrate to facilitate the parallel detection of Aβ and AICD products from PS1-/-/PS2-/- cells co-transfected with either PS1 or PS2, we observed that while PS1 generates more total Aβ product than PS2, consistent with published reports, PS1 and PS2 unexpectedly generate equal amounts of AICD product. We also observed that PS1 and PS2 produce equivalent amounts of Notch intracellular domain (NICD), indicating equal cleavage activity at the Notch S3-site (the corollary of the APP ε-site). Our findings suggest that processivity differences between PS1 and PS2 underlie the differential production of Aβ peptide. Taken together these findings offer novel insights into γ- secretase biology and have important implications for therapeutically targeting γ-secretase.
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9(4): Pp. 500 - 506
R. Douglas Shytle, Jun Tan, Paula C. Bickford, Kavon Rezai-zadeh, L Hou, Jin Zeng, Paul R. Sanberg, Cyndy D. Sanberg, Randall S. Alberte, Ryan C. Fink and Bill Roschek Jr
[Open Access Plus] |
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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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8(7): Pp. 771 - 780
M. Gaudig, U. Richarz, J. Han, B. Van Baelen and B. Schauble
[Open Access Plus] |
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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 Alzheimers disease (AD). In Study 1 (GAL-USA-11; n723), patients continuously treated with galantamine 16 mg/day exhibited a mean (± standard error [SE]) improvement in 11-item cognitive subscale of the Alzheimers 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 Clinicians 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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8(2): Pp. 175 - 186
S. Kavanagh, I. Howe, H. R. Brashear, D. Wang, B. Van Baelen, M. Todd and S. Schwalen
[Open Access Plus] |
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Background: This analysis aimed to identify an operational, clinically relevant definition of response achieved in short-term clinical trials to support the identification of patients with Alzheimers disease (AD) who would benefit most from long-term galantamine therapy. Methods: Data were analyzed from 6 randomized placebo-controlled trials of up to 6 months duration, which included patients with mild to moderate AD receiving maintenance doses of galantamine 16-24 mg/day, and from 12 open-label extensions (galantamine 24 mg/day maintenance therapy). Assessments included changes from baseline in the 11-item AD Assessment Scale-Cognitive subscale (ADAS-Cog 11). Results: Pooled analysis of the 5- 6 month trial data showed that at the trial endpoint (2-5 months after reaching maintenance doses), the proportions of galantamine- (n=1,173) versus placebo-treated patients (n=801) with probable AD categorized according to “improved”, “stable” or “non-rapid decline” criteria, were 45.8% versus 27.2%, 59.5% versus 37.1%, and 87.6% versus 69.7%, respectively (observed cases analysis), whilst changes in ADAS-Cog 11 scores versus baseline were -4.9, -4.7 and -2.9 points, respectively, for “improved”, “stable” and “non-rapid decline” galantamine-treated patients (-1.5 points for galantamine recipients overall). “Improved” or “stable” galantamine-treated patients displayed mean improvement in ADAS-Cog 11 scores over baseline until 18 months after starting treatment, and attenuated deterioration thereafter; for galantaminetreated patients exhibiting “non-rapid decline”, mean ADAS-Cog 11 score returned to baseline after approximately 12 months. Conclusions: Patients who demonstrate improvement, stability, or limited cognitive decline 2-5 months after reaching maintenance doses of galantamine are more likely to experience continued benefit from long-term galantamine therapy.
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8(3): Pp. 246 - 251
A. M. Isaacs, P. Johannsen, I. Holm, J. E. Nielsen and FReJA Consortium
[Open Access Plus] |
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CHMP2B mutations are a rare cause of autosomal dominant frontotemporal dementia (FTD). The best studied example is frontotemporal dementia linked to chromosome 3 (FTD-3) which occurs in a large Danish family, with a further CHMP2B mutation identified in an unrelated Belgian familial FTD patient. These mutations lead to C-terminal truncations of the CHMP2B protein and we will review recent advances in our understanding of the molecular effects of these mutant truncated proteins on vesicular fusion events within the endosome-lysosome and autophagy degradation pathways. We will also review the clinical features of FTD caused by CHMP2B truncation mutations as well as new brain imaging and neuropathological findings. Finally, we collate the current data on CHMP2B missense mutations, which have been reported in FTD and motor neuron disease.
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6(4): Pp. 347 - 361
Shannon L. Risacher, Andrew J. Saykin, John D. Wes, Li Shen, Hiram A. Firpi and Brenna C. McDonald
[Open Access Plus] |
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The Alzheimers Disease Neuroimaging Initiative (ADNI) is a multi-center study assessing neuroimaging in diagnosis and longitudinal monitoring. Amnestic Mild Cognitive Impairment (MCI) often represents a prodromal form of dementia, conferring a 10-15% annual risk of converting to probable AD. We analyzed baseline 1.5T MRI scans in 693 participants from the ADNI cohort divided into four groups by baseline diagnosis and one year MCI to probable AD conversion status to identify neuroimaging phenotypes associated with MCI and AD and potential predictive markers of imminent conversion. MP-RAGE scans were analyzed using publicly available voxel-based morphometry (VBM) and automated parcellation methods. Measures included global and hippocampal grey matter (GM) density, hippocampal and amygdalar volumes, and cortical thickness values from entorhinal cortex and other temporal and parietal lobe regions. The overall pattern of structural MRI changes in MCI (n=339) and AD (n=148) compared to healthy controls (HC, n=206) was similar to prior findings in smaller samples. MCI-Converters (n=62) demonstrated a very similar pattern of atrophic changes to the AD group up to a year before meeting clinical criteria for AD. Finally, a comparison of effect sizes for contrasts between the MCI-Converters and MCI-Stable (n=277) groups on MRI metrics indicated that degree of neurodegeneration of medial temporal structures was the best antecedent MRI marker of imminent conversion, with decreased hippocampal volume (left > right) being the most robust. Validation of imaging biomarkers is important as they can help enrich clinical trials of disease modifying agents by identifying individuals at highest risk for progression to AD.
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6(3): Pp. 302 - 311
K. Shudo, H. Fukasawa, M. Nakagomi and N. Yamagata
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Alzheimers disease(AD) is associated with a variety of pathophysiological features, including amyloid plaques, inflammation, immunological changes, cell death and regeneration processes, altered neurotransmission, and agerelated changes. Retinoic acid receptors (RARs) and retinoids are relevant to all of these. Here we review the pathology, pharmacology, and biochemistry of AD in relation to RARs and retinoids, and we suggest that retinoids are candidate drugs for treatment of AD.
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6(2): Pp. 171 - 178
Manuel Sarasa and Pedro Pesini
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The most common animal models currently used for Alzheimer disease (AD) research are transgenic mice that express a mutant form of human Aβ precursor protein (APP) and/or some of the enzymes implicated in their metabolic processing. However, these transgenic mice carry their own APP and APP-processing enzymes, which may interfere in the production of different amyloid-beta (Aβ) peptides encoded by the human transgenes. Additionally, the genetic backgrounds of the different transgenic mice are a possible confounding factor with regard to crucial aspects of AD that they may (or may not) reproduce. Thus, although the usefulness of transgenic mice is undisputed, we hypothesized that additional relevant information on the physiopathology of AD could be obtained from other natural non-transgenic models. We have analyzed the chick embryo and the dog, which may be better experimental models because their enzymatic machinery for processing APP is almost identical to that of humans. The chick embryo is extremely easy to access and manipulate. It could be an advantageous natural model in which to study the cell biology and developmental function of APP and a potential assay system for drugs that regulate APP processing. The dog suffers from an age-related syndrome of cognitive dysfunction that naturally reproduces key aspects of AD including Aβ cortical pathology, neuronal degeneration and learning and memory disabilities. However, dense core neuritic plaques and neurofibrillary tangles have not been consistently demonstrated in the dog. Thus, these species may be natural models with which to study the biology of AD, and could also serve as assay systems for Aβ-targeted drugs or new therapeutic strategies against this devastating disease.
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6(2): Pp. 144 - 151
Bruno Vellas, R. Black, Leon J. Thal, Nick C. Fox, M. Daniels, G. McLennan, C. Tompkins, C. Leibman, M. Pomfret and Michael Grundman
[Open Access Plus] |
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Background: Immunization of patients with Alzheimers disease (AD) with synthetic amyloid-β peptide (Aβ42) (AN1792) was previously studied in a randomized, double-blind, placebo-controlled phase 2a clinical trial, Study AN1792(QS-21)-201. Treatment was discontinued following reports of encephalitis. One year follow-up revealed that AN1792 antibody responders showed improvements in cognitive measures as assessed by the neuropsychological test battery (NTB) and a decrease in brain volume compared with placebo. Methods: A follow-up study, Study AN1792(QS-21)-251, was conducted to assess the long-term functional, psychometric, neuroimaging, and safety outcomes of patients from the phase 2a study 4.6 years after immunization with AN1792. The results were analyzed by comparing patients originally identified as antibody responders in the AN1792 phase 2a study with placebo-treated patients. Results: One hundred and fifty-nine patients/caregivers (30 placebo; 129 AN1792) participated in this follow-up study. Of the 129 AN1792-treated patients, 25 were classified in the phase 2a study as antibody responders (anti-AN1792 titers 1:2,200 at any time after the first injection). Low but detectable, sustained anti- AN1792 titers were found in 17 of 19 samples obtained from patients classified as antibody responders in the phase 2a study. No detectable anti-AN1792 antibodies were found in patients not classified as antibody responders in the phase 2a study. Significantly less decline was observed on the Disability Assessment for Dementia scale among antibody responders than placebo-treated patients (p=0.015) after 4.6 years. Significant differences in favor of responders were also observed on the Dependence Scale (p=0.033). Of the small number of patients who underwent a follow-up MRI, antibody responders showed similar brain volume loss during the follow-up period subsequent to the AN1792 phase 2a study compared with placebo-treated patients. Conclusions: Approximately 4.6 years after immunization with AN1792, patients defined as responders in the phase 2a study maintained low but detectable, sustained anti-AN1792 antibody titers and demonstrated significantly reduced functional decline compared with placebo-treated patients. Brain volume loss in antibody responders was not significantly different from placebo-treated patients approximately 3.6 years from the end of the original study. No further cases of encephalitis were noted. These data support the hypothesis that Aβ immunotherapy may have long-term functional benefits.
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5(3): Pp. 251 - 259
Luc Bousset, Jimmy Savistchenko and Ronald Melki
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The proteins Ure2, Sup35 and Rnq1 from the bakers yeast have infectious properties, termed prions, at the origin of heritable and transmissible phenotypic changes. It is widely believed that prion properties arise from the assembly of Ure2p, Sup35p and Rnq1p into insoluble fibrils. Yeast prions possess regions crucial for their propagation that can be either N- or C-terminal. These regions have unusual amino acid composition. They are very rich in glutamine and asparagine residues and resemble in that to huntingtin, a protein involved in the neurodegenerative Huntingtons disease. Yeast prions assembly process has been hypothesized to be the consequence of the properties of glutamines and asparagines to engage in polar protein-protein interactions, termed polar-zippers. While this can certainly occur under certain conditions, glutamine and asparagine residues can establish other kinds of interactions with a variety of amino acid residues thus mediating protein-protein interactions involved in the assembly of polypeptide chains into high molecular weight oligomers. This review details the interactions that can be established by glutamine and asparagine residues that may allow a better understanding of their role in mediating protein-protein interactions and prion propagation.
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2(5): Pp. 559 - 569
Ing-Feng Chang and Huo-Yen Hsiao
[Open Access Plus] |
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Novel experiments with Ultrasound Associated with High Frequency Electromagnetic Field (UAHFEMF) irradiation on rats and mice found evidences of characteristic Alzheimers disease (AD) degenerations including neurite plaques, beta-amyloid, TAU plaque and deposition in cells, Neuro-Fibrillary Tangle and Paired Helical Filament (PHF) with rats and mice irradiated up to 2454 hours. Concomitant passive avoidance test was performed on six mice, and all showed signs of visual and auditory agnosia and lost cognition of threatening condition. The post section Thioflavin-S fluorescent microscopy found dilated ventricles and dense amyloid-deposition in Ca3 and dentate gyrus. In addition, PHF was identified in the 2454 hours-irradiated rat brain by electron microscope. A human T-cell activation RhoGTPaseactivating protein (TAGAP) isoform b homolog (GenBank accession &# P84107) induced in the UAHFEMF-treated rat brain was identified using electron spray ionization (ESI) liquid chromatography tandem mass spectrometry (LC/MS/MS). We hypothesized that one of the causes of AD can be the UAHFEMF discharges in human brain.
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4(2): Pp. 205 - 212
Philip W. Landfield, Eric M. Blalock, Kuey-Chu Chen and Nada M. Porter
[Open Access Plus] |
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The original glucocorticoid (GC) hypothesis of brain aging and Alzheimers disease proposed that chronic exposure to GCs promotes hippocampal aging and AD. This proposition arose from a study correlating increasing plasma corticosterone with hippocampal astrocyte reactivity in aging rats. Numerous subsequent studies have found evidence consistent with this hypothesis, in animal models and in humans. However, several results emerged that were inconsistent with the hypothesis, highlighting the need for a more definitive test with a broader panel of biomarkers. We used microarray analyses to identify a panel of hippocampal gene expression changes that were aging-dependent, and also corticosterone- dependent. These data enabled us to test a key prediction of the GC hypothesis, namely, that the expression of most target biomarkers of brain aging should be regulated in the same direction (increased or decreased) by both GCs and aging. This prediction was decisively contradicted, as a majority of biomarker genes were regulated in opposite directions by aging and GCs, particularly inflammatory and astrocyte-specific genes. Thus, the initial hypothesis of simple positive cooperativity between GCs and aging must be rejected. Instead, our microarray data suggest that in the brain GCs and aging interact in more complex ways that depend on the cell type. Therefore, we propose a new version of the GC-brain aging hypothesis; its main premise is that aging selectively increases GC efficacy in some cell types (e.g., neurons), enhancing catabolic processes, whereas aging selectively decreases GC efficacy in other cell types (e.g., astrocytes), weakening GC anti-inflammatory activity. We also propose that changes in GC efficacy might be mediated in part by cell type specific shifts in the antagonistic balance between GC and insulin actions, which may be of relevance for Alzheimers disease pathogenesis.
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3(3): Pp. 205 - 214
Laura K. Wing, Heather A. Behanna, Linda J. Van Eldik, D. Martin Watterson and Hantamalala Ralay Ranaivo
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There is immediate potential to enhance success and innovation in drug development by pairing newly emerging approaches in medicinal chemistry and computational biology with knowledge gained from the recent era of high throughput screens and the early years of modern drug discovery when in vivo efficacy was an early "Go/No Go" project management decision. Focused, in-parallel synthetic chemistry platforms, combined with computational analyses serving as decision aids in planning, minimize the total number of compounds synthesized while maximizing the probability of creating bioavailable compounds that sample diverse chemical space. Incorporating a hierarchal strategy that emphasizes early selection of synthesized compounds based on biological or biophysical endpoints presents fewer and more relevant compounds for secondary evaluation of in vivo efficacy using animal screens with disease relevant or clinically translatable endpoints. We summarize here an interdisciplinary approach at the chemistry-biology interface that is used for the rapid discovery of novel lead compounds for neurodegenerative disorders, such as Alzheimers disease (AD). The chemistry platform uses established chemistries amenable to in-parallel strategies to create synthetic diversifications of the privileged pyridazine chemotype that sample a restricted chemical space. The hierarchal biology platform uses primary screens for in vitro activity and selectivity with the target cell type, and rapid secondary screens for in vivo efficacy and toxicity in animal models with good phenotypic penetrance for disease relevant pathophysiological endpoints or clinically translatable surrogate endpoints. For the AD case study, novel lead compounds were developed in less than two years by a small academic group, and corporate sponsored clinical trials are planned.
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