THE PATHOLOGICAL PATHWAY FOR THE PERSISTENCE OF AD SYMPTOMS AFTER THE REMOVAL OF AMYLOID PLAQUES
Keywords:
Cholinergic depletion, Excitotoxicity, NFTs, Amyloid plaque, Positive feedback mechanismAbstract
Amyloid plaque has been an indicative hallmark for Alzheimer’s diseases (AD), however the removal of which has shown to be inefficient in altering the progression of disease; thus, the study will focus on the mechanism behind the persistence of AD. The study examines the causal relationships among Aβ, neurofibrillary tangles (NFTs), cholinergic depletion, and excitotoxicity. Using secondary data from pre-existing studies, it is evidenced that Aβ causes cholinergic depletion, NFTs, and excitotoxicity through interacting with ChaT & nAChRs, IP3-K & GSK-3β, and NR1 subunit on NMDAR respectively; NFTs causes cholinergic depletion and excitotoxicity through mitochondrial dysfunction, and interaction with vGLUT respectively; while excitotoxicity causes NFTs through interaction with cdk5 and PP2A. It is concluded that the persistence of AD after Aβ removal is due to a positive feedback loop mechanism between NFTs and excitotoxicity, which causes the persistence of NFTs, cholinergic depletion, and excitotoxicity. However, the principle causative agent of AD’s progression remains undecidable.References
[1] Puig K L, Combs C K. Expression and function of APP and its metabolites outside the central nervous system. Experimental gerontology, 2013, 48(7): 608-611.
[2] O'Brien R J, Wong P C. Amyloid precursor protein processing and Alzheimer's disease. Annual review of neuroscience, 2011, 34: 185-204.
[3] Frisoni G B. Biomarker trajectories across stages of Alzheimer disease. Nature Reviews Neurology, 2012, 8(6): 299-300.
[4] Drubin D G, Kirschner M W. Tau protein function in living cells. Journal of Cell Biology, 1986, 103(6): 2739-2746.
[5] Cong Y, Liang J, Gao Y, et al. Tau in Alzheimer's disease: Mechanisms and therapeutic strategies. Current Alzheimer Research, 2018, 15(3): 283-300.
[6] Potter P E, Rauschkolb P K, Pandya Y, et al. Pre-and post-synaptic cortical cholinergic deficits are proportional to amyloid plaque presence and density at preclinical stages of Alzheimer's disease. Acta neuropathologica, 2011, 122(1): 49-60.
[7] Bowen D M, Benton JS, Spillane JA, et al. Choline acetyltransferase activity and histopathology of frontal neocortex from biopsies of demented patients. Journal of the neurological sciences, 1982, 57(2-3): 191-202.
[8] Heneka M T, O’Banion M K, Terwel D, et al. Neuroinflammatory processes in Alzheimer’s disease. Journal of neural transmission, 2010, 117(8): 919-947.
[9] Ong W-Y, Tanaka K,Dawe G S ,et al. Slow excitotoxicity in Alzheimer's disease. Journal of Alzheimer's Disease, 2013, 35(4): 643-668.
[10] Whitehouse P J. The cholinergic deficit in Alzheimer's disease. The Journal of clinical psychiatry, 1998.
[11] Evin G, Kenche VB. BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease. Medicinal research reviews, 2020, 40(1): 339-384.
[12] Doody R S, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. New England Journal of Medicine, 2013, 369(4): 341-350.
[13] Egan M F, Kost J, Voss T, et al. Randomized trial of verubecestat for prodromal Alzheimer’s disease. New England Journal of Medicine, 2019, 380(15): 1408-1420.
[14] McGeer J, McGeer E, Rogers M A, et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. New England Journal of Medicine, 2001, 345(21): 1515-1521.
[15] Jordan F, Quinn T J, McGuinness B, et al. Aspirin, steroidal and nonsteroidal anti‐inflammatory drugs for the treatment of Alzheimer's disease. Cochrane Database of Systematic Reviews, 2012, 2.
[16] Stuve O, Weideman R A, McMahan DM,et al. Diclofenac reduces the risk of Alzheimer’s disease: a pilot analysis of NSAIDs in two US veteran populations. Therapeutic advances in neurological disorders, 2020, 13: 1756286420935676.
[17] Hampel H, Ewers M, Bürger K, et al. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. Journal of Clinical Psychiatry, 2009, 70(6): 922.
[18] Wischik C M, Seng C M, Seng S W,et al. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease. Journal of Alzheimer's Disease, 2015, 44(2): 705-720.
[19] Gonneaud J, Arenaza-Urquijo EM, Mezenge F, et al. Increased florbetapir binding in the temporal neocortex from age 20 to 60 years. Neurology, 2017, 89(24): 2438-2446.
[20] Jansen W J, Gonneaud J, Kramer J, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a metaanalysis. Jama, 2015, 313(19): 1924-1938.
[21] Teipel S, Meindl S, Grinberg C. et al. Mild cognitive impairment in the elderly is associated with volume loss of the cholinergic basal forebrain region. Biological psychiatry, 2010, 67(6): 588-591.
[22] Mazère J, Prunier C, BarretO, et al. In vivo SPECT imaging of vesicular acetylcholine transporter using [123I]-IBVM in early Alzheimer's disease. Neuroimage, 2008, 40(1): 280-288.
[23] Davis K L, Mohs R C, Marin D, et al. Cholinergic markers in elderly patients with early signs of Alzheimer disease. Jama, 1999, 281(15): 1401-1406.
[24] Francis P T, Palmer A M, Snape M, et al. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. Journal of Neurology, Neurosurgery & Psychiatry, 1999, 66(2): 137-147.
[25] Pettit D L, Shao Z, Yakel J L. β-Amyloid1–42 peptide directly modulates nicotinic receptors in the rat hippocampal slice. Journal of Neuroscience, 2001, 21(1): RC120-RC120.
[26] Pike C J, Burdick D, Walencewicz A J, et al. Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. Journal of Neuroscience, 1993, 13(4): 1676-1687.
[27] Zheng W-H, Quirion R. Amyloid β peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. Neuroscience, 2002, 115(1): 201-211.
[28] Baudier J, Cole R D. Phosphorylation of tau proteins to a state like that in Alzheimer's brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids. Journal of Biological Chemistry, 1987, 262(36): 17577-17583.
[29] Takashima A, Noguchi K, Sato K,et al. Exposure of rat hippocampal neurons to amyloid β peptide (25–35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3β. Neuroscience letters, 1996, 203(1): 33-36.
[30] Leroy K, Yilmaz Z, Brion J-P. Increased level of active GSK‐3β in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of