Molecular Insights into the Inhibition and Disaggregation Effects of EGCG on A40 and A42 Cofibrillation

The misfolding and aggregation of amyloid-beta (A beta) peptides play a pivotal role in the pathogenesis of Alzheimer's disease (AD). A beta 40 and A beta 42, the two primary isoforms of A beta, 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 A beta 40 and A beta 42 peptides and disaggregate their homogeneous fibrils. However, its effects on the cofibrillation of A beta 40 and A beta 42 have not yet been explored. Here, we employed molecular dynamic simulations to investigate the effects of EGCG on the coaggregation of A beta 40 and A beta 42, as well as on their mixed fibril. Our findings indicated that EGCG effectively inhibits the codimerization of A beta 40 and A beta 42 primarily by impeding the interchain interaction between the two isoforms. The key binding sites for EGCG on A beta 40 and A beta 42 are the polar residues and aromatic residues, engaging in hydrogen-bond , pi-pi, and cation-pi interactions with EGCG. Additionally, EGCG disaggregates the A beta 40-A beta 42 mixed fibril by reducing its long-range interaction through similar binding sites and interactions as those between EGCG and A beta 40-A beta 42 heterodimers. Our research reveals the comprehensive inhibition and disaggregation effects of EGCG on the cofibrillation of A beta isoforms, which provides further support for the development of EGCG as an effective antiaggregation agent for AD.