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

Abstract

The self-aggregation of amyloid beta (A beta) proteins has played a crucial role in the pathogenesis of Alzheimer's diseases. Despite previous studies on the aggregation process of A beta proteins, little is known about how the cross-interaction between A beta isoforms affects the aggregation pathways and the resulting structures of A beta aggregates. Here, we study the cross-interaction between A beta 40 and A beta 42 during their aggregation process by measuring the aggregation kinetics and the structures of A beta aggregates under varied concentrations of A beta isoform proteins in their mixture. We found that the mixture of A beta 40 and A beta 42 monomers results in the concentration-dependent aggregation process leading to different aggregate structures in such a way that the different concentrations of A beta 40 and A beta 42 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 A beta 40 (or A beta 42) oligomer and fibril seeds in the aggregation pathway of A beta 42 (or A beta 40). We show that the oligomer (or fibril) seed affects not only the aggregation kinetics but also the structures of A beta aggregates. Our study sheds light on the cross-interaction between A beta isoforms at primary nucleation level and its role in the aggregation pathways.