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CNS & Neurological Disorders - Drug Targets

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ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

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Systematic Review Article

A Systematic Review of Updated Mechanistic Insights Towards Alzheimer’s Disease

Author(s): Arun Mittal*, Rupali Sharma, Satish Sardana, Parveen Kumar Goyal, Mona Piplani and Anima Pandey

Volume 22, Issue 8, 2023

Published on: 05 July, 2022

Page: [1232 - 1242] Pages: 11

DOI: 10.2174/1871527321666220510144127

open access plus

Abstract

Background: Alzheimer's disease (AD) is a degenerative neurological disorder that impairs memory, cognitive abilities, and the ability to do everyday activities. This neurodegenerative disease is growing increasingly common as the world's population ages. Here, we reviewed some of the key findings showing the function of Aβ peptide, oxidative stress, free radical damage Triggering Receptors Expressed cn Myeloid Cells 2 (TREM2), Nitric Oxide (NO) and gut microbiota in the aetiology of AD.

Methods: The potentially relevant online medical databases, namely PubMed, Scopus, Google Scholar, Cochrane Library, and JSTOR, were exhaustively researched. In addition, the data reported in the present study were primarily intervened on the basis of the timeline selected from 1 January 2000 to 31 October 2021. The whole framework was designed substantially based on key terms and studies selected by virtue of their relevance to our investigations.

Results: Findings suggested that channels of free radicals, such as transition metal accumulation and genetic factors, are mainly accountable for the redox imbalance that assist to understand better the pathogenesis of AD and incorporating new therapeutic approaches. Moreover, TREM2 might elicit a protective function for microglia in AD. NO causes an increase in oxidative stress and mitochondrial damage, compromising cellular integrity and viability. The study also explored that the gut and CNS communicate with one another and that regulating gut commensal flora might be a viable therapeutic for neurodegenerative illnesses like AD.

Conclusion: There are presently no viable therapies for Alzheimer's disease, but recent breakthroughs in our knowledge of the disease's pathophysiology may aid in the discovery of prospective therapeutic targets.

Keywords: CNS, TREMZ, alzheimer, neurofibrillary tangles, amyloid β, lysosomal membrane.

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[1]
Alzheimer A. Uber eine eigenartige Erkrankung der Hirnrinde. Allg Zeitschr f Psychiatrieu Psych-Gerichtl Med 1907; 64: 146-8.
[2]
Hyman BT, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 2012; 8(1): 1-13.
[http://dx.doi.org/10.1016/j.jalz.2011.10.007] [PMID: 22265587]
[3]
Scheltens P, Blennow K, Breteler MMB, et al. Alzheimer’s disease. Lancet 2016; 388(10043): 505-17.
[http://dx.doi.org/10.1016/S0140-6736(15)01124-1] [PMID: 26921134]
[4]
WHO. Dementia. 2021. Available from: https://www.who.int/news-room/fact-sheets/detail/dementia (Accessed on: December 27, 2021).
[5]
WHO. ICD-11 - ICD-11 for mortality and morbidity statistics. 2021. Available from: https://icd.who.int/browse11/l-m/en#/http%3A%2F%2Fid.who.int%2Ficd%2Fentity%2F546689346 (Accessed on: November 19, 2021).
[6]
Puglielli L, Tanzi RE, Kovacs DM. Alzheimer’s disease: The cholesterol connection. Nat Neurosci 2003; 6(4): 345-51.
[http://dx.doi.org/10.1038/nn0403-345] [PMID: 12658281]
[7]
Luchsinger JA, Mayeux R. Dietary factors and Alzheimer’s disease. Lancet Neurol 2004; 3(10): 579-87.
[http://dx.doi.org/10.1016/S1474-4422(04)00878-6] [PMID: 15380154]
[8]
Shobab LA, Hsiung GYR, Feldman HH. Cholesterol in Alzheimer’s disease. Lancet Neurol 2005; 4(12): 841-52.
[http://dx.doi.org/10.1016/S1474-4422(05)70248-9] [PMID: 16297842]
[9]
Ledesma MD, Dotti CG. Amyloid excess in Alzheimer’s disease: What is cholesterol to be blamed for? FEBS Lett 2006; 580(23): 5525-32.
[http://dx.doi.org/10.1016/j.febslet.2006.06.038] [PMID: 16814780]
[10]
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease. Neurology 1984; 34(7): 939-44.
[http://dx.doi.org/10.1212/WNL.34.7.939] [PMID: 6610841]
[11]
Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: Revising the NINCDS-ADRDA criteria. Lancet Neurol 2007; 6(8): 734-46.
[http://dx.doi.org/10.1016/S1474-4422(07)70178-3] [PMID: 17616482]
[12]
Murman DL, Colenda CC. The economic impact of neuropsychiatric symptoms in Alzheimer’s disease: Can drugs ease the burden? Pharm Eco 2005; 23(3): 227-42.
[http://dx.doi.org/10.2165/00019053-200523030-00004] [PMID: 15836005]
[13]
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021; 372: n71.
[http://dx.doi.org/10.1136/bmj.n71] [PMID: 33782057]
[14]
Glenner GG, Wong CW. Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120(3): 885-90.
[http://dx.doi.org/10.1016/S0006-291X(84)80190-4] [PMID: 6375662]
[15]
Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 1985; 82(12): 4245-9.
[http://dx.doi.org/10.1073/pnas.82.12.4245] [PMID: 3159021]
[16]
Hernández-Zimbrón LF, Rivas-Arancibia S. Deciphering an interplay of proteins associated with amyloid β 1-42 peptide and molecular mechanisms of Alzheimer’s disease. Rev Neurosci 2014; 25(6): 773-83.
[http://dx.doi.org/10.1515/revneuro-2014-0025] [PMID: 25010778]
[17]
Esch FS, Keim PS, Beattie EC, et al. Cleavage of amyloid β peptide during constitutive processing of its precursor. Science 1990; 248(4959): 1122-4.
[http://dx.doi.org/10.1126/science.2111583] [PMID: 2111583]
[18]
Sisodia SS. β-amyloid precursor protein cleavage by a membranebound protease. Proc Natl Acad Sci USA 1992; 89(13): 6075-9.
[http://dx.doi.org/10.1073/pnas.89.13.6075] [PMID: 1631093]
[19]
Kuhn PH, Wang H, Dislich B, et al. ADAM10 is the physiologically relevant, constitutive α-secretase of the amyloid precursor protein in primary neurons. EMBO J 2010; 29(17): 3020-32.
[http://dx.doi.org/10.1038/emboj.2010.167] [PMID: 20676056]
[20]
Kawahara M, Kuroda Y. Molecular mechanism of neurodegeneration induced by Alzheimer’s β-amyloid protein: Channel formation and disruption of calcium homeostasis. Brain Res Bull 2000; 53(4): 389-97.
[http://dx.doi.org/10.1016/S0361-9230(00)00370-1] [PMID: 11136994]
[21]
Glabe C. Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease. J Mol Neurosci 2001; 17(2): 137-45.
[http://dx.doi.org/10.1385/JMN:17:2:137] [PMID: 11816787]
[22]
Small SA, Gandy S. Sorting through the cell biology of Alzheimer’s disease: Intracellular pathways to pathogenesis. Neuron 2006; 52(1): 15-31.
[http://dx.doi.org/10.1016/j.neuron.2006.09.001] [PMID: 17015224]
[23]
Palop JJ, Mucke L. Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: From synapses toward neural networks. Nat Neurosci 2010; 13(7): 812-8.
[http://dx.doi.org/10.1038/nn.2583] [PMID: 20581818]
[24]
Kwok JBJ, Halliday GM, Brooks WS, et al. Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer’s disease with non-cored plaques and no neuritic dystrophy. J Biol Chem 2003; 278(9): 6748-54.
[http://dx.doi.org/10.1074/jbc.M211827200] [PMID: 12493737]
[25]
Van Broeck B, Van Broeckhoven C, Kumar-Singh S. Current insights into molecular mechanisms of Alzheimer disease and their implications for therapeutic approaches. Neurodegener Dis 2007; 4(5): 349-65.
[http://dx.doi.org/10.1159/000105156] [PMID: 17622778]
[26]
Newman M, Musgrave IF, Lardelli M. Alzheimer disease: Amyloidogenesis, the presenilins and animal models. Biochim Biophys Acta 2007; 1772(3): 285-97.
[http://dx.doi.org/10.1016/j.bbadis.2006.12.001] [PMID: 17208417]
[27]
Ji WU, Stephen MS. Amyloid-β induced signaling by cellular prion protein and Fyn kinase in Alzheimer disease. Prion 2013; 37-41.
[http://dx.doi.org/10.4161/pri.22212]
[28]
Flores-Rodríguez P, Ontiveros-Torres MA, Cárdenas-Aguayo MC, et al. The relationship between truncation and phosphorylation at the C-terminus of tau protein in the paired helical filaments of Alzheimer’s disease. Front Neurosci 2015; 9: 33.
[http://dx.doi.org/10.3389/fnins.2015.00033] [PMID: 25717290]
[29]
Sarkar S. Neurofibrillary tangles mediated human neuronal tauopathies: Insights from fly models. J Genet 2018; 97(3): 783-93.
[http://dx.doi.org/10.1007/s12041-018-0962-4] [PMID: 30027909]
[30]
Vasudevan A, Koushika SP. Molecular mechanisms governing axonal transport: A C. elegans perspective. J Neurogenet 2020; 34(3-4): 282-97.
[http://dx.doi.org/10.1080/01677063.2020.1823385] [PMID: 33030066]
[31]
Sallee MD, Feldman JL. Microtubule organization across cell types and states. Curr Biol 2021; 31(10): R506-11.
[http://dx.doi.org/10.1016/j.cub.2021.01.042] [PMID: 34033781]
[32]
Weller RO, Carare RO, Boche D. Amyloid: Vascular and Parenchymal. In: Encyclopedia of Neuroscience;. USA: Academic Press 2009; pp. 355-62.
[http://dx.doi.org/10.1016/B978-008045046-9.00105-4]
[33]
Mroczko B, Groblewska M, Litman-Zawadzka A. The role of protein misfolding and tau oligomers (TauOs) in Alzheimer’s disease (AD). Int J Mol Sci 2019; 20(19): 4661.
[http://dx.doi.org/10.3390/ijms20194661] [PMID: 31547024]
[34]
Song L, Wells EA, Robinson AS. Critical molecular and cellular contributors to tau pathology. Biomedicines 2021; 9(2): 190.
[http://dx.doi.org/10.3390/biomedicines9020190] [PMID: 33672982]
[35]
Cornejo VH, Hetz C. The unfolded protein response in Alzheimer’s disease. Semin Immunopathol 2013; 35(3): 277-92.
[http://dx.doi.org/10.1007/s00281-013-0373-9] [PMID: 23609500]
[36]
van der Kant R, Goldstein LSB, Ossenkoppele R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci 2020; 21(1): 21-35.
[http://dx.doi.org/10.1038/s41583-019-0240-3] [PMID: 31780819]
[37]
Smith MA, Rottkamp CA, Nunomura A, Raina AK, Perry G. Oxidative stress in Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis 2000; 1502(1): 139-44.
[http://dx.doi.org/10.1016/S0925-4439(00)00040-5]
[38]
Varadarajan S, Kanski J, Aksenova M, Lauderback C, Butterfield DA. Different mechanisms of oxidative stress and neurotoxicity for Alzheimer’s A β(1-42) and A β(25-35). J Am Chem Soc 2001; 123(24): 5625-31.
[http://dx.doi.org/10.1021/ja010452r] [PMID: 11403592]
[39]
Kontush A. Amyloid-β: An antioxidant that becomes a prooxidant and critically contributes to Alzheimer’s disease. Free Radic Biol Med 2001; 31(9): 1120-31.
[http://dx.doi.org/10.1016/S0891-5849(01)00688-8] [PMID: 11677045]
[40]
Butterfield DA. Amyloid β-peptide (1-42)-induced oxidative stress and neurotoxicity: Implications for neurodegeneration in Alzheimer’s disease brain. A review. Free Radic Res 2002; 36(12): 1307-13.
[http://dx.doi.org/10.1080/1071576021000049890] [PMID: 12607822]
[41]
Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid Med Cell Longev 2013; 2013: 316523.
[http://dx.doi.org/10.1155/2013/316523] [PMID: 23983897]
[42]
Ulland TK, Colonna M. TREM2 - a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 2018; 14(11): 667-75.
[http://dx.doi.org/10.1038/s41582-018-0072-1] [PMID: 30266932]
[43]
Tondo G, Perani D, Comi C. Comi C. TAM receptor pathways at the crossroads of neuroinflammation and neurodegeneration. Dis Markers 2019; 2019: 2387614.
[http://dx.doi.org/10.1155/2019/2387614] [PMID: 31636733]
[44]
Sainaghi PP, Bellan M, Lombino F, et al. Growth arrest specific 6 concentration is increased in the cerebrospinal fluid of patients with alzheimer’s disease. J Alzheimers Dis 2017; 55(1): 59-65.
[http://dx.doi.org/10.3233/JAD-160599] [PMID: 27636849]
[45]
Togo T, Katsuse O, Iseki E. Nitric oxide pathways in Alzheimer’s disease and other neurodegenerative dementias. Neurol Res 2004; 26(5): 563-6.
[http://dx.doi.org/10.1179/016164104225016236] [PMID: 15265275]
[46]
Bostanciklioğlu M. The role of gut microbiota in pathogenesis of Alzheimer’s disease. J Appl Microbiol 2019; 127(4): 954-67.
[http://dx.doi.org/10.1111/jam.14264] [PMID: 30920075]
[47]
Pluta R. Ułamek-Kozioł M, Januszewski S, Czuczwar SJ. Gut microbiota and pro/prebiotics in Alzheimer’s disease. Aging (Albany NY) 2020; 12(6): 5539-50.
[http://dx.doi.org/10.18632/aging.102930] [PMID: 32191919]
[48]
Jiang C, Li G, Huang P, Liu Z, Zhao B. The gut microbiota and Alzheimer’s disease. J Alzheimers Dis 2017; 58(1): 1-15.
[http://dx.doi.org/10.3233/JAD-161141] [PMID: 28372330]

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