Dataset Information

Inhibition of the Self-Assembly of A? and of Tau by Polyphenols: Mechanistic Studies.

ABSTRACT: The amyloid-? (A?) peptide and tau protein are thought to play key neuropathogenic roles in Alzheimer's disease (AD). Both A? and tau self-assemble to form the two major pathological hallmarks of AD: amyloid plaques and neurofibrillary tangles, respectively. In this review, we show that naturally occurring polyphenols abundant in fruits, vegetables, red wine, and tea possess the ability to target pathways associated with the formation of assemblies of A? and tau. Polyphenols modulate the enzymatic processing of the amyloid-? precursor protein and inhibit toxic A? oligomerization by enhancing the clearance of A?42 monomer, modulating monomer-monomer interactions and remodeling oligomers to non-toxic forms. Additionally, polyphenols modulate tau hyperphosphorylation and inhibit tau ?-sheet formation. The anti-A?-self-assembly and anti-tau-self-assembly effects of polyphenols increase their potential as preventive or therapeutic agents against AD, a complex disease that involves many pathological mechanisms.

SUBMITTER: Zheng Q

PROVIDER: S-EPMC6630797 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Inhibition of the Self-Assembly of Aβ and of Tau by Polyphenols: Mechanistic Studies.

Zheng Qiuchen Q Kebede Micheal T MT Kemeh Merc M MM Islam Saadman S Lee Bethany B Bleck Stuart D SD Wurfl Liliana A LA Lazo Noel D ND

Molecules (Basel, Switzerland) 20190622 12

The amyloid-β (Aβ) peptide and tau protein are thought to play key neuropathogenic roles in Alzheimer's disease (AD). Both Aβ and tau self-assemble to form the two major pathological hallmarks of AD: amyloid plaques and neurofibrillary tangles, respectively. In this review, we show that naturally occurring polyphenols abundant in fruits, vegetables, red wine, and tea possess the ability to target pathways associated with the formation of assemblies of Aβ and tau. Polyphenols modulate the enzymat ...[more]

PMID: 31234523

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Project description:While several polyphenols were found to either inhibit or modulate the aggregation of proteins implicated in neurodegenerative diseases, such as Parkinson's disease (PD), discrepant action mechanisms have been reported. This, in addition to some polyphenols' pan-assay interference compounds' reputation, casts some doubts concerning their therapeutic relevance. Here, we studied, through molecular dynamics and enhanced sampling methods, the aggregation of 11-mer peptides from the non-amyloid-β component, an aggregation-prone domain of α-synuclein (α-syn) implicated in PD and other synucleinopathies, in neat water and aqueous solutions of resveratrol (RSV) and gallic acid (GA). Further, simulations of the complete protein were carried out in aqueous urea, RSV, and GA solutions. Our results show that peptide aggregation is not disrupted by either phenolic compound. Thus, instead, intrusion of RSV and GA in the inter-peptide region induces a peptide-peptide re-orientation, favoring terminal interactions that manifest in the formation of barrierless solvent-separated configurations. Moreover, although the (poly)phenols induce a pronounced peptide dewetting at high concentrations, β-sheet-rich regions, a hallmark of α-syn aggregation, are not disrupted. Thus, our results indicate that, if anything, RSV and GA delay or modulate peptide aggregation at high concentrations via the stabilization of solvent-separated conformations as opposed to aggregation inhibition. Structural analysis of the full protein, however, shows that the (poly)phenols induce more extended conformations of α-syn, similar to urea, possibly also influencing its aggregation propensity. However, opposite to urea, the (poly)phenols reduce α-syn's conformational space, likely due to steric effects and a slowdown of the solvent dynamics. These effects are concentration-dependent and possibly unattainable at therapeutic-relevant concentrations. These results suggest that the aggregation inhibition activity of RSV and GA in vitro should involve, instead, either the non-covalent binding to oligomeric intermediates or the stabilization of the monomer and/or oligomers through the formation of covalent bonds of the respective quinones with α-syn. In addition, the enhanced aggregation tendency of the peptides observed here could be associated with the formation of non-toxic oligomers, reported for some polyphenols.

Dataset Information

Inhibition of the Self-Assembly of A? and of Tau by Polyphenols: Mechanistic Studies.

Publications

Inhibition of the Self-Assembly of Aβ and of Tau by Polyphenols: Mechanistic Studies.

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