Molecular mechanisms of resveratrol and EGCG in the inhibition of Aβ42 aggregation and disruption of Aβ42 protofibril: similarities and differences

The aggregation of amyloid-beta protein (A beta) into fibrillary deposits is implicated in Alzheimer's disease (AD), and inhibiting A beta aggregation and clearing A beta fibrils are considered as promising strategies to treat AD. It has been reported that resveratrol (RSV) and epigallocatechin-3-gallate (EGCG), two of the most extensively studied natural polyphenols, are able to inhibit A beta fibrillization and remodel the preformed fibrillary aggregates into amorphous, non-toxic species. However, the mechanisms by which RSV inhibits A beta(42) aggregation and disrupts A beta(42) protofibril, as well as the inhibitory/disruptive mechanistic similarities and differences between RSV and EGCG, remain mostly elusive. Herein, we performed extensive all-atom molecular dynamics (MD) simulations on A beta(42) dimers (the early aggregation state of A beta(42)) and protofibrils (the intermediate of A beta(42) fibril formation and elongation) in the absence/presence of RSV or EGCG molecules. Our simulations show that both RSV and EGCG can bind with A beta(42) monomers and inhibit the dimerization of A beta(42). The binding of RSV with A beta(42) peptide is mostly via pi-pi stacking interactions, while the binding of EGCG with A beta(42) is mainly through hydrophobic, pi-pi stacking, and hydrogen-bonding interactions. Moreover, both RSV and EGCG disrupt the beta-sheet structure and K28-A42 salt bridges, leading to a disruption of A beta(42) protofibril structure. RSV mainly binds with residues whose side-chains point inwards from the surface of the protofibril, while EGCG mostly binds with residues whose side-chains point outwards from the surface of the protofibril. Furthermore, RSV interacts with A beta(42) protofibrils mostly via pi-pi stacking interactions, while EGCG interacts with A beta(42) protofibrils mainly via hydrogen-bonding and hydrophobic interactions. For comparison, we also explore the effects of RSV/EGCG molecules on the aggregation inhibition and protofibril disruption of the Iowa mutant (D23N) A beta. Our findings may pave the way for the design of more effective drug candidates as well as the utilization of cocktail therapy using RSV and EGCG for the treatment of AD.

Automated summary

Resveratrol (RSV) and epigallocatechin-3-gallate (EGCG) have been found to inhibit the aggregation of amyloid-beta protein (A beta) and may be promising strategies for treating Alzheimer's disease (AD). However, the specific mechanisms of how RSV inhibits A beta(42) aggregation and disrupts A beta(42) protofibril, as well as the differences between RSV and EGCG in their inhibitory/disruptive effects, still need further investigation.