The Amyloid-β Pathway in Alzheimer’s Disease

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 26(10), P. 5481 - 5503

Published: Aug. 30, 2021

Abstract Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at center of Alzheimer’s disease (AD) pathophysiology. While detailed mechanisms and spatial-temporal dynamics leading to synaptic failure, neurodegeneration, clinical onset are still under intense investigation, established biochemical alterations Aβ cycle remain core biological hallmark AD promising targets for development disease-modifying therapies. Here, we systematically review update vast state-of-the-art literature science with evidence from basic research studies human genetic multi-modal biomarker investigations, which supports a crucial role dyshomeostasis pathophysiological dynamics. We discuss highlighting differentiated interaction distinct species other AD-related mechanisms, such as tau-mediated, neuroimmune inflammatory changes, well neurochemical imbalance. Through lens latest multimodal vivo biomarkers AD, this cross-disciplinary examines compelling hypothesis- data-driven rationale Aβ-targeting therapeutic strategies early treatment AD.

Language: Английский

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The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade

Journal of Alzheimer s Disease, Journal Year: 2018, Volume and Issue: 64(s1), P. S567 - S610

Published: June 12, 2018

The amyloid-␤ oligomer (A␤O) hypothesis was introduced in 1998.It proposed that the brain damage leading to Alzheimer's disease (AD) instigated by soluble, ligand-like A␤Os.This based on discovery fibril-free synthetic preparations of A␤Os were potent CNS neurotoxins rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death (Lambert et al., 1998).The mechanism attributed disrupted signaling involving tyrosine-protein kinase Fyn, mediated an unknown toxin receptor.Over 4,000 articles concerning have been published since then, including more than 400 reviews.A␤Os shown accumulate AD-dependent manner human and animal model tissue experimentally, impair learning memory instigate major facets AD neuropathology, tau pathology, synapse deterioration loss, inflammation, oxidative damage.As reviewed Hayden Teplow 2013, A␤O "has all but supplanted amyloid cascade."Despite emerging understanding role played pathogenesis, not yet received clinical attention given plaques, which at core attempts therapeutics diagnostics are no longer regarded as most pathogenic form A␤.However, if momentum research continues, particularly efforts elucidate key aspects structure, a clear path successful modifying therapy can be envisioned.Ensuring lessons learned from recent, late-stage failures applied appropriately throughout therapeutic development will further enable likelihood near-term.

Language: Английский

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Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation

Nature Medicine, Journal Year: 2017, Volume and Issue: 24(1), P. 29 - 38

Published: Dec. 4, 2017

Language: Английский

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The β-Secretase BACE1 in Alzheimer’s Disease

Biological Psychiatry, Journal Year: 2020, Volume and Issue: 89(8), P. 745 - 756

Published: Feb. 13, 2020

BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) was initially cloned and characterized in 1999. It is required for the generation of all monomeric forms amyloid-β (Aβ), including Aβ

Language: Английский

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Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2020, Volume and Issue: 17(1), P. 115 - 124

Published: Oct. 19, 2020

Abstract The etiology of the common, sporadic form Alzheimer's disease (sAD) is unknown. We hypothesize that tau pathology within select projection neurons with susceptible microenvironments can initiate sAD. This postulate rests on extensive data demonstrating in human brains appears about a decade before formation Aβ plaques (Aβps), especially targeting glutamate association cortex. Data from aging rhesus monkeys show abnormal phosphorylation vulnerable neurons, associated calcium dysregulation. Abnormally phosphorylated (pTau) microtubules traps APP‐containing endosomes, which increase production. As oligomers tau, this would drive vicious cycles leading to sAD over long lifespan, genetic and environmental factors may accelerate pathological events. hypothesis could be testable aged monkey cortex naturally expresses characteristics capable promoting sustaining

Language: Английский

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TREM2 function impedes tau seeding in neuritic plaques

Nature Neuroscience, Journal Year: 2019, Volume and Issue: 22(8), P. 1217 - 1222

Published: June 24, 2019

Language: Английский

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Neuropathology of Alzheimer's Disease

Neurotherapeutics, Journal Year: 2021, Volume and Issue: 19(1), P. 173 - 185

Published: Nov. 2, 2021

Language: Английский

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Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease

Nature, Journal Year: 2023, Volume and Issue: 618(7964), P. 349 - 357

Published: May 31, 2023

The incidence of Alzheimer's disease (AD), the leading cause dementia, increases rapidly with age, but why age constitutes main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and structural integrity myelin sheaths1, latter which associated secondary neuroinflammation2,3. As support axonal energy metabolism neuronal health4-7, we hypothesized that loss could be an upstream for amyloid-β (Aβ) deposition, central neuropathological hallmark AD. Here identify genetic pathways dysfunction demyelinating injuries as potent drivers amyloid deposition in mouse models Mechanistically, causes accumulation Aβ-producing machinery within swellings cleavage cortical precursor protein. Suprisingly, AD mice dysfunctional lack plaque-corralling microglia despite overall increase their numbers. Bulk single-cell transcriptomics defects show there a concomitant induction highly similar distinct disease-associated signatures specific to damage plaques, respectively. Despite successful induction, (DAM) usually clear plaques are apparently distracted nearby damage. Our data suggest working model whereby age-dependent promote Aβ plaque formation directly indirectly therefore factor. Improving oligodendrocyte health promising target delay development slow progression

Language: Английский

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Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease

Acta Neuropathologica, Journal Year: 2017, Volume and Issue: 133(6), P. 933 - 954

Published: March 4, 2017

Language: Английский

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Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with Aβ Pathology

Neuron, Journal Year: 2019, Volume and Issue: 105(2), P. 260 - 275.e6

Published: Nov. 20, 2019

Language: Английский

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