Insights into the cross-amyloid aggregation of AB40 and its N-terminal truncated peptide A?11-40 affected by epigallocatechin gallate

Inhibition of protein misfolding and aggregation is a great challenge in the field of biochemical and biopharmaceutical engineering. Alzheimer???s disease (AD) is a protein-misfolding disease, and the interactions between 40-amino-acid-residue B-amyloid peptide (AB40) and its N-terminal truncated peptide AB11-40 demonstrate that AB11-40 may play an important role in the pathological process of AD. However, the effect of inhibitors on AB11-40 aggregation and on the cross-amyloid aggregation (coassembly) between AB40 and AB11-40 has never been studied. Herein, coaggregation and seeding interactions between AB40 and AB11-40 as well as the effect of epigallocatechin gallate (EGCG), a small molecule inhibitor, on the cross-amyloid aggregation have been investigated by extensive analyses. It is found that AB11-40 participates in the aggregation of AB40 and leads to the formation of coaggregates that contain less B-sheet structures than pure AB40 aggregates. The aggregation kinetics along with morphologies and secondary structures of the coaggregates are also significantly affected by the AB40/AB11-40 ratio. EGCG accelerates the nucleation of AB40 but retards that of AB11-40 by affecting their elongation and secondary nucleation processes in solution and on solid surfaces. Meanwhile, EGCG makes the conformations of the seeding-induced AB aggregates more compact, especially for the homologous seedings. Isothermal titration calorimetry measurement indicates that hydrophobic interactions mainly contribute to the inhibition of the two AB isoforms by EGCG. The findings of this research have provided new insights into AB aggregation and the effect of an important inhibitor and the results would benefit in the development of potent inhibitors against co-assembly of different amyloid proteins. ?? 2021 The Chemical Industry and Engineering Society of China, and Chemical Industry Press Co., Ltd. All rights reserved.

Automated summary

Inhibition of protein misfolding and aggregation is a major challenge in biochemical and biopharmaceutical engineering. This study investigated the coaggregation and seeding interactions between AB40 and AB11-40, as well as the effect of the small molecule inhibitor EGCG on amyloid aggregation. The results showed that AB11-40 participates in the aggregation of AB40 and that EGCG inhibits both AB isoforms mainly through hydrophobic interactions. These findings provide new insights into AB aggregation and have implications for the development of inhibitors against amyloid protein co-assembly.