Molecular insight into cross-interaction between amyloid β isoforms and its effect on aggregation pathways.

Abstract

The self-aggregation of amyloid β (Aβ) proteins has played a crucial role in the pathogenesis of Alzheimer's diseases. Despite previous studies on the aggregation process of Aβ proteins, little is known about how the cross-interaction between Aβ isoforms affects the aggregation pathways and the resulting structures of Aβ aggregates. Here, we study the cross-interaction between Aβ40 and Aβ42 during their aggregation process by measuring the aggregation kinetics and the structures of Aβ aggregates under varied concentrations of Aβ isoform proteins in their mixture. We found that the mixture of Aβ40 and Aβ42 monomers results in the concentration-dependent aggregation process leading to different aggregate structures in such a way that the different concentrations of Aβ40 and Aβ42 induce the different structural types of aggregates such as different sized oligomers or fibrils with their different morphologies and flexibilities. Moreover, we investigate the effect of Aβ40 (or Aβ42) oligomer and fibril seeds in the aggregation pathway of Aβ42 (or Aβ40). We show that the oligomer (or fibril) seed affects not only the aggregation kinetics but also the structures of Aβ aggregates. Our study sheds light on the cross-interaction between Aβ isoforms at primary nucleation level and its role in the aggregation pathways.