The Toxicity and Polymorphism of β-Amyloid Oligomers

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(12), P. 4477 - 4477

Published: June 24, 2020

It is widely accepted that β-amyloid oligomers (Aβos) play a key role in the progression of Alzheimer's disease (AD) by inducing neuron damage and cognitive impairment, but Aβos are highly heterogeneous their size, structure cytotoxicity, making corresponding studies tough to carry out. Nevertheless, number have recently made remarkable progress describing characteristics pathogenicity Aβos. We here review mechanisms which exert neuropathogenesis for AD progression, including receptor binding, cell membrane destruction, mitochondrial damage, Ca2+ homeostasis dysregulation tau pathological induction. also summarize such as morphology cytotoxicity dimers, trimers, Aβ*56 spherical oligomers, suggest may different at phases pathogenesis, resulting differential consequences on neuronal synaptotoxicity survival. warranted investigate temporal sequence human brain examine relationship between impairment.

Language: Английский

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A first order phase transition mechanism underlies protein aggregation in mammalian cells

eLife, Journal Year: 2019, Volume and Issue: 8

Published: Feb. 4, 2019

The formation of misfolded protein aggregates is a hallmark neurodegenerative diseases. aggregate process exhibits an initial lag phase when precursor clusters spontaneously assemble. However, most experimental assays are blind to this phase. We develop quantitative assay based on super-resolution imaging in fixed cells and light sheet living study the early steps aggregation mammalian cells. find that even under normal growth conditions have clusters. cluster size distribution precisely expected for so-called super-saturated system first order transition. This means there exists nucleation barrier, critical above which grow mature. Homeostasis maintained through Szilard model entailing preferential clearance super-critical uncover role putative chaperone (RuvBL) disassembly large results indicate behave like condensates. Editorial note: article has been editorial authors decide how respond issues raised during peer review. Reviewing Editor's assessment all addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

Language: Английский

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Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

Molecules, Journal Year: 2020, Volume and Issue: 25(7), P. 1659 - 1659

Published: April 3, 2020

The structural polymorphism and the physiological pathophysiological roles of two important proteins, β-amyloid (Aβ) tau, that play a key role in Alzheimer’s disease (AD) are reviewed. Recent results demonstrate monomeric Aβ has functions. Toxic oligomeric assemblies (AβOs) may decisive AD pathogenesis. polymorph fibrillar (fAβ) form very ordered cross-β structure is assumed to be non-toxic. Tau monomers also have several actions; however, their oligomerization leads toxic oligomers (TauOs). Further polymerization probably non-toxic structures, among others neurofibrillary tangles (NFTs). Their was determined by cryo-electron microscopy at atomic level. Both AβOs TauOs initiate neurodegenerative processes, interactions crosstalk determine changes AD. (perhaps AβO) prionoid character, they responsible for cell-to-cell spreading disease. extra- intracellular (and not previously hypothesized amyloid plaques NFTs) represent novel targets drug research.

Language: Английский

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Mechanism of amyloid protein aggregation and the role of inhibitors

Pure and Applied Chemistry, Journal Year: 2019, Volume and Issue: 91(2), P. 211 - 229

Published: Feb. 1, 2019

Abstract Inhibition of amyloid β peptide (Aβ) aggregation is an important goal due to the connection this process with Alzheimer’s disease. Traditionally, inhibitors were developed aim retard overall macroscopic aggregation. However, recent advances imply that approaches based on mechanistic insights may be more powerful. In such approaches, microscopic steps underlying are identified, and it established which these step(s) lead neurotoxicity. Inhibitors then derived specifically target involved in toxicity. The Aβ composed at minimum three steps: primary nucleation monomers only, secondary fibril surface, elongation fibrils by monomer addition. vast majority toxic species generated from process: a key inhibit order limit nucleation, delays emergence without affecting their total concentration, also effective. instead increase toxicity over time. Here we briefly review findings regarding Aβ, its dominance attempts derive

Language: Английский

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The role of amyloid oligomers in neurodegenerative pathologies

International Journal of Biological Macromolecules, Journal Year: 2021, Volume and Issue: 181, P. 582 - 604

Published: March 23, 2021

Many neurodegenerative diseases are rooted in the activities of amyloid-like proteins which possess conformations that spread to healthy proteins. These include Alzheimer's disease (AD), Parkinson's (PD), Huntington's (HD) and amyotrophic lateral sclerosis (ALS). While their clinical manifestations vary, protein-level mechanisms remarkably similar. Aberrant monomeric undergo conformational shifts, facilitating aggregation formation solid fibrils. However, there is growing evidence intermediate oligomeric stages key drivers neuronal toxicity. Analysis protein dynamics complicated by fact nucleation growth not a linear pathway. Feedback within this pathway results exponential acceleration aggregation, but exerted oligomers fibrils can alter cellular interactions environment as whole. The resulting cascade effects likely contributes late onset accelerating progression disorders widespread they have on body. In review we explore associated with AD, PD, HD ALS, well common aggregation. From this, identify core elements pathological been targeted for therapies, may become future therapeutic targets.

Language: Английский

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