Insights into the cross-amyloid aggregation of Aβ40 and its N-terminal truncated peptide Aβ11-40 affected by epigallocatechin gallate

Abstract

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 β-amyloid peptide (Aβ40) and its N-terminal truncated peptide Aβ11-40 demonstrate that Aβ11-40 may play an important role in the pathological process of AD. However, the effect of inhibitors on Aβ11-40 aggregation and on the cross-amyloid aggregation (co-assembly) between Aβ40 and Aβ11-40 has never been studied. Herein, coaggregation and seeding interactions between Aβ40 and Aβ11-40 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 Aβ11-40 participates in the aggregation of Aβ40 and leads to the formation of coaggregates that contain less β-sheet structures than pure Aβ40 aggregates. The aggregation kinetics along with morphologies and secondary structures of the coaggregates are also significantly affected by the Aβ40/Aβ11-40 ratio. EGCG accelerates the nucleation of Aβ40 but retards that of Aβ11-40 by affecting their elongation and secondary nucleation processes in solution and on solid surfaces. Meanwhile, EGCG makes the conformations of the seeding-induced Aβ aggregates more compact, especially for the homologous seedings. Isothermal titration calorimetry measurement indicates that hydrophobic interactions mainly contribute to the inhibition of the two Aβ isoforms by EGCG. The findings of this research have provided new insights into Aβ 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.