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Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Review Article

Current Status of Alzheimer’s Disease and Pathological Mechanisms Investigating the Therapeutic Molecular Targets

Author(s): Shivani Bagga and Manish Kumar*

Volume 23, Issue 6, 2023

Published on: 10 August, 2022

Page: [492 - 508] Pages: 17

DOI: 10.2174/1566524022666220404112843

Price: $65

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Abstract

Alzheimer's disease (AD) is a psychological, biological, or developmental disorder that affects basic mental functioning. AD is generally affiliated with marked discomfort and impaired social, professional, or other crucial aspects of life. AD is predominant worldwide, but a disparity in prevalence is observed amongst nations. Around 3/4 of people with Alzheimer's disease are from underdeveloped nations, which receive only 1/10th of global mental health resources. Residents of each community and age category share their presence in the overall load of AD. AD is a multifactorial disease impacted by numerous environmental, genetic, and endogenous elements. Heteromorphic interactive downstream cascades, networks, and molecular mechanisms (inflammation and immune network, cholinergic deficit, lipid transit, endocytosis, excitotoxicity, oxidative stress, amyloid and tau pathology, energy metabolism, neuron and synapse loss, and cell death) have been isolated, imparting a non-dissociative contribution in pathogenesis of AD. In the CNS, the structural organization of cholinergic neurons can give a novel insight into the mechanism of new learning. The alleviation of central cholinergic transposal following destruction in the basal forebrain cholinergic neurons precipitates a decline in neurocognitive symptoms visible in AD patients. The brain of patients suffering from AD exhibits plaques of aggregated amyloid-β and neurofibrillary tangles containing hyperphosphorylated tau protein. Amyloid-β triggers cholinergic loss by modulation of calcium and generation of cell-damaging molecules such as nitric oxide and reactive oxygen species intermediates. The present review focuses on the pathogenic mechanisms related to stages, diagnosis, and therapeutic approaches involved in AD.

Keywords: Alzheimer’s disease, oxidative stress, inflammation, amyloidogenic, tauopathy, cholinergic deficits, memory, dementia.

[1]
Jahn H. Memory loss in Alzheimer’s disease. Dialogues Clin Neurosci 2013; 15(4): 445-54.
[http://dx.doi.org/10.31887/DCNS.2013.15.4/hjahn] [PMID: 24459411]
[2]
Šimić G, Babić Leko M, Wray S, et al. Tau protein hyperphosphorylation and aggregation in Alzheimer’s disease and other tauopathies, and possible neuroprotective strategies. Biomolecules 2016; 6(1): 6.
[http://dx.doi.org/10.3390/biom6010006] [PMID: 26751493]
[3]
Nichols E, Szoeke CEI, Vollset SE, et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18(1): 88-106.
[http://dx.doi.org/10.1016/S1474-4422(18)30403-4] [PMID: 30497964]
[4]
Fiest KM, Roberts JI, Maxwell CJ, et al. The prevalence and incidence of dementia due to Alzheimer’s disease: A systematic review and meta-analysis. Can J Neurol Sci 2016; 43(1) (Suppl. 1): S51-82.
[http://dx.doi.org/10.1017/cjn.2016.36] [PMID: 27307128]
[5]
Wang L, Bharti, KR, Pavlov PF, Winblad B. Small molecule therapeutics for tauopathy in Alzheimer’s disease: Walking on the path of most resistance. Eur J Med Chem 2021; 209: 112915.
[http://dx.doi.org/10.1016/j.ejmech.2020.112915] [PMID: 33139110]
[6]
Kimura N. Diabetes mellitus induces Alzheimer’s disease pathology: Histopathological evidence from animal models. Int J Mol Sci 2016; 17(4): 503.
[http://dx.doi.org/10.3390/ijms17040503] [PMID: 27058526]
[7]
Shingo AS, Kanabayashi T, Kito S, Murase T. Intracerebroventricular administration of an insulin analogue recovers STZ-induced cognitive decline in rats. Behav Brain Res 2013; 241: 105-11.
[http://dx.doi.org/10.1016/j.bbr.2012.12.005] [PMID: 23238038]
[8]
Kozlov S, Afonin A, Evsyukov I, Bondarenko A. Alzheimer’s disease: As it was in the beginning. Rev Neurosci 2017; 28(8): 825-43.
[http://dx.doi.org/10.1515/revneuro-2017-0006] [PMID: 28704198]
[9]
Frota NAF, Nitrini R, Damasceno BP, et al. Criteria for the diagnosis of Alzheimer’s disease: Recommendations of the scientific department of cognitive neurology and aging of the Brazilian academy of neurology. Dement Neuropsychol 2011; 5(3): 146-52.
[http://dx.doi.org/10.1590/S1980-57642011DN05030002] [PMID: 29213739]
[10]
Cece Y, Shifu X. Are the revised diagnostic criteria for Alzheimer’s disease useful in low- and middle-income countries? Shanghai Jingshen Yixue 2015; 27(2): 119-23.
[http://dx.doi.org/10.11919/j.issn.1002-0829.215001] [PMID: 26120262]
[11]
Solomon A, Mangialasche F, Richard E, et al. Advances in the prevention of Alzheimer’s disease and dementia. J Intern Med 2014; 275(3): 229-50.
[http://dx.doi.org/10.1111/joim.12178] [PMID: 24605807]
[12]
Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018; 14(4): 535-62.
[http://dx.doi.org/10.1016/j.jalz.2018.02.018] [PMID: 29653606]
[13]
Rabbito A, Dulewicz M, Kulczyńska-Przybik A, Mroczko B. Biochemical markers in Alzheimer’s disease. Int J Mol Sci 2020; 21(6): 1989.
[http://dx.doi.org/10.3390/ijms21061989] [PMID: 32183332]
[14]
Ballinger E, Ananth M, Talmage DA, Role L. Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline. Neuron 2016; 91(6): 1199-218.
[http://dx.doi.org/10.1016/j.neuron.2016.09.006]
[15]
Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: Cholinergic signaling shapes nervous system function and behavior. Neuron 2012; 76(1): 116-29.
[http://dx.doi.org/10.1016/j.neuron.2012.08.036] [PMID: 23040810]
[16]
Blake MG, Boccia MM. Basal forebrain cholinergic system and memory. Behavioral neuroscience of learning and memory: Current topics in behavioral neurosciences. Switzerland: Springer International Publishing 2016; 37: 253-73.
[http://dx.doi.org/10.1007/7854_2016_467]
[17]
Ferreira-Vieira TH, Guimaraes IM, Silva FR, Ribeiro FM. Alzheimer’s disease: Targeting the cholinergic system. Curr Neuropharmacol 2016; 14(1): 101-15.
[http://dx.doi.org/10.2174/1570159X13666150716165726] [PMID: 26813123]
[18]
Chen XQ, Mobley WC. Exploring the pathogenesis of Alzheimer disease in basal forebrain cholinergic neurons: Converging insights from alternative hypotheses. Front Neurosci 2019; 13: 446.
[http://dx.doi.org/10.3389/fnins.2019.00446] [PMID: 31133787]
[19]
Triaca V, Ruberti F, Canu N. NGF and the amyloid precursor protein in Alzheimer’s disease: From molecular players to neuronal circuits. Adv Exp Med Biol 2021; 1331: 145-65.
[http://dx.doi.org/10.1007/978-3-030-74046-7_10] [PMID: 34453297]
[20]
Haam J, Yakel JL. Cholinergic modulation of the hippocampal region and memory function. J Neurochem 2017; 142 (Suppl. 2): 111-21.
[http://dx.doi.org/10.1111/jnc.14052] [PMID: 28791706]
[21]
Stanciu GD, Luca A, Rusu RN, et al. Alzheimer’s disease pharmacotherapy in relation to cholinergic system involvement. Biomolecules 2019; 10(1): 40.
[http://dx.doi.org/10.3390/biom10010040] [PMID: 31888102]
[22]
Wang R, Reddy PH. Role of glutamate and NMDA receptors in Alzheimer’s disease. J Alzheimers Dis 2017; 57(4): 1041-8.
[http://dx.doi.org/10.3233/JAD-160763] [PMID: 27662322]
[23]
Liu J, Chang L, Song Y, Li H, Wu Y. The role of NMDA receptors in Alzheimer’s disease. Front Neurosci 2019; 13: 43.
[http://dx.doi.org/10.3389/fnins.2019.00043] [PMID: 30800052]
[24]
Bukke VN, Archana M, Villani R, et al. The dual role of glutamatergic neurotransmission in Alzheimer’s disease: From pathophysiology to pharmacotherapy. Int J Mol Sci 2020; 21(20): 7452.
[http://dx.doi.org/10.3390/ijms21207452] [PMID: 33050345]
[25]
Findley CA, Bartke A, Hascup KN, Hascup ER. Amyloid beta-related alterations to glutamate signaling dynamics during Alzheimer’s disease progression. ASN Neuro 2019; 11: 1759091419855541.
[http://dx.doi.org/10.1177/1759091419855541] [PMID: 31213067]
[26]
Cho Y, Bae HG, Okun E, Arumugam TV, Jo DG. Physiology and pharmacology of amyloid precursor protein. Pharmacol Ther 2022; 235: 108122.
[http://dx.doi.org/10.1016/j.pharmthera.2022.108122] [PMID: 35114285]
[27]
Islam S, Sun Y, Gao Y, et al. Presenilin is essential for ApoE secretion, a novel role of presenilin involved in Alzheimer's disease pathogenesis. J Neurosci 2022; JN-RM-2039-21.
[http://dx.doi.org/10.1523/JNEUROSCI.2039-21.2021]
[28]
Esparza TJ, Wildburger NC, Jiang H, et al. Soluble amyloid-beta aggregates from human Alzheimer’s disease brains. Sci Rep 2016; 6(1): 38187.
[http://dx.doi.org/10.1038/srep38187] [PMID: 27917876]
[29]
Povala G, Bellaver B, De Bastiani MA, et al. Soluble amyloid-beta isoforms predict downstream Alzheimer’s disease pathology. Cell Biosci 2021; 11(1): 204.
[http://dx.doi.org/10.1186/s13578-021-00712-3] [PMID: 34895338]
[30]
Cárdenas-Aguayo MC, Gómez-Virgilio L, DeRosa S, Meraz-Ríos MA. The role of tau oligomers in the onset of Alzheimer’s disease neuropathology. ACS Chem Neurosci 2014; 5(12): 1178-91.
[http://dx.doi.org/10.1021/cn500148z] [PMID: 25268947]
[31]
Iqbal K, Liu F, Gong CX. Tau and neurodegenerative disease: The story so far. Nat Rev Neurol 2016; 12(1): 15-27.
[http://dx.doi.org/10.1038/nrneurol.2015.225] [PMID: 26635213]
[32]
Gaikwad S, Puangmalai N, Bittar A, et al. Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer’s disease and frontotemporal dementia. Cell Rep 2021; 36(3): 109419.
[http://dx.doi.org/10.1016/j.celrep.2021.109419] [PMID: 34289368]
[33]
Shafiei SS, Guerrero-Muñoz MJ, Castillo-Carranza DL. Tau oligomers: Cytotoxicity, propagation, and mitochondrial damage. Front Aging Neurosci 2017; 9: 83.
[http://dx.doi.org/10.3389/fnagi.2017.00083] [PMID: 28420982]
[34]
Hill E, Wall MJ, Moffat KG, Karikari TK. Understanding the pathophysiological actions of tau oligomers: A critical review of current electrophysiological approaches. Front Mol Neurosci 2020; 13: 155.
[http://dx.doi.org/10.3389/fnmol.2020.00155] [PMID: 32973448]
[35]
Gyparaki MT, Arab A, Sorokina EM, et al. Tau forms oligomeric complexes on microtubules that are distinct from tau aggregates. Proc Natl Acad Sci USA 2021; 118(19): e2021461118.
[http://dx.doi.org/10.1073/pnas.2021461118] [PMID: 33952699]
[36]
Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: Where do we go from here? Nat Rev Neurol 2021; 17(3): 157-72.
[http://dx.doi.org/10.1038/s41582-020-00435-y] [PMID: 33318676]
[37]
Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Mol Neurodegener 2020; 15(1): 40.
[http://dx.doi.org/10.1186/s13024-020-00391-7] [PMID: 32677986]
[38]
Van Eldik LJ, Carrillo MC, Cole PE, et al. The roles of inflammation and immune mechanisms in Alzheimer’s disease. Alzheimers Dement 2016; 2(2): 99-109.
[http://dx.doi.org/10.1016/j.trci.2016.05.001] [PMID: 29067297]
[39]
Neniskyte U, Vilalta A, Brown GC. Tumour necrosis factor alpha-induced neuronal loss is mediated by microglial phagocytosis. FEBS Lett 2014; 588(17): 2952-6.
[http://dx.doi.org/10.1016/j.febslet.2014.05.046] [PMID: 24911209]
[40]
Zotova E, Nicoll JA, Kalaria R, Holmes C, Boche D. Inflammation in Alzheimer’s disease: Relevance to pathogenesis and therapy. Alzheimers Res Ther 2010; 2(1): 1-9.
[http://dx.doi.org/10.1186/alzrt24] [PMID: 20122289]
[41]
Ju Hwang C, Choi DY, Park MH, Hong JT. NF-κB as a key mediator of brain inflammation in Alzheimer’s disease. CNS Neurol Disord Drug Targets 2019; 18(1): 3-10.
[http://dx.doi.org/10.2174/1871527316666170807130011] [PMID: 28782486]
[42]
Javed H, Khan MM, Ahmad A, et al. Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. Neuroscience 2012; 210: 340-52.
[http://dx.doi.org/10.1016/j.neuroscience.2012.02.046] [PMID: 22441036]
[43]
Chen CH, Zhou W, Liu S, et al. Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer’s disease. Int J Neuropsychopharmacol 2012; 15(1): 77-90.
[http://dx.doi.org/10.1017/S1461145711000149] [PMID: 21329555]
[44]
Jha NK, Jha SK, Kar R, Nand P, Swati K, Goswami VK. Nuclear factor-kappa β as a therapeutic target for Alzheimer’s disease. J Neurochem 2019; 150(2): 113-37.
[http://dx.doi.org/10.1111/jnc.14687] [PMID: 30802950]
[45]
Kumar M, Bansal N. Implications of phosphoinositide 3-kinase-Akt (PI3K-Akt) pathway in the pathogenesis of Alzheimer’s disease. Mol Neurobiol 2022; 59(1): 354-85.
[http://dx.doi.org/10.1007/s12035-021-02611-7] [PMID: 34699027]
[46]
Cianciulli A, Porro C, Calvello R, Trotta T, Lofrumento DD, Panaro MA. Microglia mediated neuroinflammation: Focus on PI3K modulation. Biomolecules 2020; 10(1): 137.
[http://dx.doi.org/10.3390/biom10010137] [PMID: 31947676]
[47]
Razani E, Pourbagheri-Sigaroodi A, Safaroghli-Azar A, Zoghi A, Shanaki-Bavarsad M, Bashash D. The PI3K/Akt signaling axis in Alzheimer’s disease: A valuable target to stimulate or suppress? Cell Stress Chaperones 2021; 26(6): 871-87.
[http://dx.doi.org/10.1007/s12192-021-01231-3] [PMID: 34386944]
[48]
Cui H, Kong Y, Zhang H. Oxidative stress, mitochondrial dysfunction, and aging. J Signal Transduct 2012; 2012: 646354.
[http://dx.doi.org/10.1155/2012/646354] [PMID: 21977319]
[49]
Sultana R, Perluigi M, Butterfield DA. Lipid peroxidation triggers neurodegeneration: A redox proteomics view into the Alzheimer disease brain. Free Radic Biol Med 2013; 62: 157-69.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.09.027] [PMID: 23044265]
[50]
Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014; 2014: 360438.
[http://dx.doi.org/10.1155/2014/360438] [PMID: 24999379]
[51]
Petrovic S, Arsic A, Ristic-Medic D, Cvetkovic Z, Vucic V. Lipid peroxidation and antioxidant supplementation in neurodegenerative diseases: A review of human studies. Antioxidants 2020; 9(11): 1128.
[http://dx.doi.org/10.3390/antiox9111128] [PMID: 33202952]
[52]
Zheng J, Hu CL, Shanley KL, Bizzozero OA. Mechanism of protein carbonylation in glutathione-depleted rat brain slices. Neurochem Res 2018; 43(3): 609-18.
[http://dx.doi.org/10.1007/s11064-017-2456-9] [PMID: 29264677]
[53]
Haddad M, Hervé V, Ben Khedher MR, Rabanel JM, Ramassamy C. Glutathione: An old and small molecule with great functions and new applications in the brain and in Alzheimer’s disease. Antioxid Redox Signal 2021; 35(4): 270-92.
[http://dx.doi.org/10.1089/ars.2020.8129] [PMID: 33637005]
[54]
Huang WJ, Zhang X, Chen WW. Role of oxidative stress in Alzheimer’s disease. Biomed Rep 2016; 4(5): 519-22.
[http://dx.doi.org/10.3892/br.2016.630] [PMID: 27123241]
[55]
Pocernich CB, Butterfield DA. Elevation of glutathione as a therapeutic strategy in Alzheimer disease. Biochim Biophys Acta 2012; 1822(5): 625-30.
[http://dx.doi.org/10.1016/j.bbadis.2011.10.003] [PMID: 22015471]
[56]
Forman HJ, Zhang H. Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy. Nat Rev Drug Discov 2021; 20(9): 689-709.
[http://dx.doi.org/10.1038/s41573-021-00233-1] [PMID: 34194012]
[57]
Bradley-Whitman MA, Lovell MA. Biomarkers of lipid peroxidation in Alzheimer disease (AD): An update. Arch Toxicol 2015; 89(7): 1035-44.
[http://dx.doi.org/10.1007/s00204-015-1517-6] [PMID: 25895140]
[58]
Mandal PK, Tripathi M, Sugunan S. Brain oxidative stress: Detection and mapping of anti-oxidant marker ‘Glutathione’ in different brain regions of healthy male/female, MCI and Alzheimer patients using non-invasive magnetic resonance spectroscopy. Biochem Biophys Res Commun 2012; 417(1): 43-8.
[http://dx.doi.org/10.1016/j.bbrc.2011.11.047] [PMID: 22120629]
[59]
Colizzi C. The protective effects of polyphenols on Alzheimer’s disease: A systematic review. Alzheimers Dement 2018; 5(1): 184-96.
[http://dx.doi.org/10.1016/j.trci.2018.09.002] [PMID: 31194101]
[60]
Silva RFM, Pogačnik L. Polyphenols from food and natural products: Neuroprotection and safety. Antioxidants 2020; 9(1): 61.
[http://dx.doi.org/10.3390/antiox9010061] [PMID: 31936711]
[61]
Dubey H, Gulati K, Ray A. Alzheimer’s disease: A contextual link with nitric oxide synthase. Curr Mol Med 2020; 20(7): 505-15.
[http://dx.doi.org/10.2174/1566524019666191129103117] [PMID: 31782366]
[62]
Cioffi F, Adam RHI, Bansal R, Broersen K. A review of oxidative stress products and related genes in early Alzheimer’s disease. J Alzheimers Dis 2021; 83(3): 977-1001.
[http://dx.doi.org/10.3233/JAD-210497] [PMID: 34420962]
[63]
Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta 2014; 1842(8): 1240-7.
[http://dx.doi.org/10.1016/j.bbadis.2013.10.015] [PMID: 24189435]
[64]
Grossberg GT, Tong G, Burke AD, Tariot PN. Present algorithms and future treatments for Alzheimer’s disease. J Alzheimers Dis 2019; 67(4): 1157-71.
[http://dx.doi.org/10.3233/JAD-180903] [PMID: 30741683]
[65]
Chen J, Luo B, Zhong BR, et al. Sulfuretin exerts diversified functions in the processing of amyloid precursor protein. Genes Dis 2020; 8(6): 867-81.
[http://dx.doi.org/10.1016/j.gendis.2020.11.008] [PMID: 34522714]
[66]
Hafez Ghoran S, Kijjoa A. Marine-derived compounds with anti-Alzheimer’s disease activities. Mar Drugs 2021; 19(8): 410.
[http://dx.doi.org/10.3390/md19080410] [PMID: 34436249]
[67]
Bai L, Liu R, Wang R, et al. Attenuation of Pb-induced Aβ generation and autophagic dysfunction via activation of SIRT1: Neuroprotective properties of resveratrol. Ecotoxicol Environ Saf 2021; 222: 112511.
[http://dx.doi.org/10.1016/j.ecoenv.2021.112511] [PMID: 34273848]
[68]
Liu C, Cheng ZY, Xia QP, Hu YH, Wang C, He L. GPR40 receptor agonist TAK-875 improves cognitive deficits and reduces β-amyloid production in APPswe/PS1dE9 mice. Psychopharmacology 2021; 238(8): 2133-46.
[http://dx.doi.org/10.1007/s00213-021-05837-4] [PMID: 34173034]
[69]
McKinzie DL, Winneroski LL, Green SJ, et al. Discovery and early clinical development of LY3202626, a low-dose, CNS-penetrant BACE inhibitor. J Med Chem 2021; 64(12): 8076-100.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00489] [PMID: 34081466]
[70]
Mycroft-West CJ, Devlin AJ, Cooper LC, et al. Glycosaminoglycans from Litopenaeus vannamei inhibit the Alzheimer’s disease β secretase, BACE1. Mar Drugs 2021; 19(4): 203.
[http://dx.doi.org/10.3390/md19040203] [PMID: 33916819]
[71]
Mycroft-West CJ, Devlin AJ, Cooper LC, et al. Inhibition of BACE1, the β-secretase implicated in Alzheimer’s disease, by a chondroitin sulfate extract from Sardina pilchardus. Neural Regen Res 2020; 15(8): 1546-53.
[http://dx.doi.org/10.4103/1673-5374.274341] [PMID: 31997821]
[72]
Yan R, Vassar R. Targeting the β secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol 2014; 13(3): 319-29.
[http://dx.doi.org/10.1016/S1474-4422(13)70276-X] [PMID: 24556009]
[73]
Elfiky AM, Mahmoud AA, Elreedy HA, Ibrahim KS, Ghazy MA. Quercetin stimulates the non-amyloidogenic pathway via activation of ADAM10 and ADAM17 gene expression in aluminum chloride-induced Alzheimer’s disease rat model. Life Sci 2021; 285: 119964.
[http://dx.doi.org/10.1016/j.lfs.2021.119964] [PMID: 34537230]
[74]
Postina R. Activation of α-secretase cleavage. J Neurochem 2012; 120(1) (Suppl. 1): 46-54.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07459.x] [PMID: 21883223]
[75]
Chun YS, Cho YY, Kwon OH, Zhao D, Yang HO, Chung S. Substrate-specific activation of α-secretase by 7-deoxy-trans-dihydronarciclasine increases non-amyloidogenic processing of β-amyloid protein precursor. Molecules 2020; 25(3): 646.
[http://dx.doi.org/10.3390/molecules25030646] [PMID: 32028607]
[76]
Wang YQ, Qu DH, Wang K. Therapeutic approaches to Alzheimer’s disease through stimulating of non-amyloidogenic processing of amyloid precursor protein. Eur Rev Med Pharmacol Sci 2016; 20(11): 2389-403.
[PMID: 27338066]
[77]
Saretz S, Basset G, Useini L, et al. Modulation of γ-secretase activity by a carborane-based flurbiprofen analogue. Molecules 2021; 26(10): 2843.
[http://dx.doi.org/10.3390/molecules26102843] [PMID: 34064783]
[78]
Maia MA, Sousa E. BACE-1 and γ-secretase as therapeutic targets for Alzheimer’s disease. Pharmaceuticals (Basel) 2019; 12(1): 41.
[http://dx.doi.org/10.3390/ph12010041] [PMID: 30893882]
[79]
Spencer B, Masliah E. Immunotherapy for Alzheimer’s disease: Past, present and future. Front Aging Neurosci 2014; 6: 114.
[http://dx.doi.org/10.3389/fnagi.2014.00114] [PMID: 24959143]
[80]
Zhao J, Liu X, Xia W, Zhang Y, Wang C. Targeting amyloidogenic processing of APP in Alzheimer’s disease. Front Mol Neurosci 2020; 13: 137.
[http://dx.doi.org/10.3389/fnmol.2020.00137] [PMID: 32848600]
[81]
Marciani DJ. Promising results from Alzheimer’s disease passive immunotherapy support the development of a preventive vaccine. Research 2019; 2019: 5341375.
[http://dx.doi.org/10.34133/2019/5341375] [PMID: 31549066]
[82]
Nalivaeva NN, Turner AJ. Targeting amyloid clearance in Alzheimer’s disease as a therapeutic strategy. Br J Pharmacol 2019; 176(18): 3447-63.
[http://dx.doi.org/10.1111/bph.14593] [PMID: 30710367]
[83]
Shi J, Sabbagh MN, Vellas B. Alzheimer’s disease beyond amyloid: Strategies for future therapeutic interventions. BMJ 2020; 371: m3684.
[http://dx.doi.org/10.1136/bmj.m3684] [PMID: 33036984]
[84]
Fagiani F, Lanni C, Racchi M, Govoni S. Targeting dementias through cancer kinases inhibition. Alzheimers Dement 2020; 6(1): e12044.
[http://dx.doi.org/10.1002/trc2.12044] [PMID: 32671184]
[85]
Hepp Rehfeldt SC, Majolo F, Goettert MI, Laufer S. c-Jun N-terminal kinase inhibitors as potential leads for new therapeutics for Alzheimer’s diseases. Int J Mol Sci 2020; 21(24): 9677.
[http://dx.doi.org/10.3390/ijms21249677] [PMID: 33352989]
[86]
Panza F, Seripa D, Solfrizzi V, et al. Tau aggregation inhibitors: The future of Alzheimer’s pharmacotherapy? Expert Opin Pharmacother 2016; 17(4): 457-61.
[http://dx.doi.org/10.1517/14656566.2016.1146686] [PMID: 26809554]
[87]
Soeda Y, Takashima A. New insights into drug discovery targeting tau protein. Front Mol Neurosci 2020; 13: 590896.
[http://dx.doi.org/10.3389/fnmol.2020.590896] [PMID: 33343298]
[88]
Spangenberg E, Severson PL, Hohsfield LA, et al. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. Nat Commun 2019; 10(1): 3758.
[http://dx.doi.org/10.1038/s41467-019-11674-z] [PMID: 31434879]
[89]
Burstein AH, Sabbagh M, Andrews R, Valcarce C, Dunn I, Altstiel L. Development of Azeliragon, an oral small molecule antagonist of the receptor for advanced glycation endproducts, for the potential slowing of loss of cognition in mild Alzheimer’s disease. J Prev Alzheimers Dis 2018; 5(2): 149-54.
[http://dx.doi.org/10.14283/jpad.2018.18] [PMID: 29616709]
[90]
Kume T. Therapeutic potential of the activators of the nuclear factor erythroid 2-related factor 2-antioxidant response element pathway in brain disorders. Biol Pharm Bull 2017; 40(5): 553-6.
[http://dx.doi.org/10.1248/bpb.b17-00091] [PMID: 28458340]
[91]
van Dyck CH. Anti-amyloid-β monoclonal antibodies for Alzheimer’s disease: Pitfalls and promise. Biol Psychiatry 2018; 83(4): 311-9.
[http://dx.doi.org/10.1016/j.biopsych.2017.08.010] [PMID: 28967385]
[92]
Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K. Alzheimer’s disease drug development pipeline: 2020. Alzheimers Dement 2020; 6(1): e12050.
[http://dx.doi.org/10.1002/trc2.12050] [PMID: 32695874]
[93]
Hampel H, Vassar R, De Strooper B, et al. The β-secretase BACE1 in Alzheimer’s disease. Biol Psychiatry 2021; 89(8): 745-56.
[http://dx.doi.org/10.1016/j.biopsych.2020.02.001] [PMID: 32223911]
[94]
Spitzer P, Walter M, Göth C, et al. Pharmacological inhibition of amyloidogenic APP processing and knock-down of APP in primary human macrophages impairs the secretion of cytokines. Front Immunol 2020; 11: 1967.
[http://dx.doi.org/10.3389/fimmu.2020.01967] [PMID: 33013850]
[95]
Winblad B, Graf A, Riviere ME, Andreasen N, Ryan JM. Active immunotherapy options for Alzheimer’s disease. Alzheimers Res Ther 2014; 6(1): 7.
[http://dx.doi.org/10.1186/alzrt237] [PMID: 24476230]
[96]
Kabir MT, Uddin MS, Mathew B, Das PK, Perveen A, Ashraf GM. Emerging promise of immunotherapy for Alzheimer’s disease: A new hope for the development of Alzheimer’s vaccine. Curr Top Med Chem 2020; 20(13): 1214-34.
[http://dx.doi.org/10.2174/1568026620666200422105156] [PMID: 32321405]
[97]
Cacabelos R. How plausible is an Alzheimer’s disease vaccine? Expert Opin Drug Discov 2020; 15(1): 1-6.
[http://dx.doi.org/10.1080/17460441.2019.1667329] [PMID: 31526140]
[98]
Novick PA, Lopes DH, Branson KM, et al. Design of β-amyloid aggregation inhibitors from a predicted structural motif. J Med Chem 2012; 55(7): 3002-10.
[http://dx.doi.org/10.1021/jm201332p] [PMID: 22420626]
[99]
Sales TA, Prandi IG, Castro AA, et al. Recent developments in metal-based drugs and chelating agents for neurodegenerative diseases treatments. Int J Mol Sci 2019; 20(8): 1829.
[http://dx.doi.org/10.3390/ijms20081829] [PMID: 31013856]
[100]
Congdon EE, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 2018; 14(7): 399-415.
[http://dx.doi.org/10.1038/s41582-018-0013-z] [PMID: 29895964]
[101]
Sharma S. Role of extracellular vesicles in Alzheimer’s disease: Current advances. Curr Mol Med 2022; 22(2): 85-97.
[http://dx.doi.org/10.2174/1566524021666210406121807] [PMID: 33823777]
[102]
Zhang A, Park S, Sullivan JE, Jing S. The effectiveness of problem-solving therapy for primary care patients depressive and/or anxiety disorders: A systematic review and meta-analysis. J Am Board Fam Med 2018; 31(1): 139-50.
[http://dx.doi.org/10.3122/jabfm.2018.01.170270] [PMID: 29330248]

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