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Molecular Insights into the Inhibition and Disaggregation Effects of EGCG on Aβ40 and Aβ42 Cofibrillation

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journal contribution
posted on 2024-02-15, 19:09 authored by Xuhua Li, Yu Zhang, Yuetian Wang, Shengli Zhang, Lei Zhang
The misfolding and aggregation of amyloid-β (Aβ) peptides play a pivotal role in the pathogenesis of Alzheimer’s disease (AD). Aβ40 and Aβ42, the two primary isoforms of Aβ, can not only self-aggregate into homogeneous aggregates but also coaggregate to form mixed fibrils. Epigallocatechin-3-gallate (EGCG), a prominent tea polyphenol, has shown the capability to prevent the self-aggregation of Aβ40 and Aβ42 peptides and disaggregate their homogeneous fibrils. However, its effects on the cofibrillation of Aβ40 and Aβ42 have not yet been explored. Here, we employed molecular dynamic simulations to investigate the effects of EGCG on the coaggregation of Aβ40 and Aβ42, as well as on their mixed fibril. Our findings indicated that EGCG effectively inhibits the codimerization of Aβ40 and Aβ42 primarily by impeding the interchain interaction between the two isoforms. The key binding sites for EGCG on Aβ40 and Aβ42 are the polar residues and aromatic residues, engaging in hydrogen-bond , π–π, and cation-π interactions with EGCG. Additionally, EGCG disaggregates the Aβ40-Aβ42 mixed fibril by reducing its long-range interaction through similar binding sites and interactions as those between EGCG and Aβ40-Aβ42 heterodimers. Our research reveals the comprehensive inhibition and disaggregation effects of EGCG on the cofibrillation of Aβ isoforms, which provides further support for the development of EGCG as an effective antiaggregation agent for AD.

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