Insights into the coaggregation mechanisms of amyloid-α and amyloid-β

The aggregation of amyloid-β protein (Aβ) into oligomers and amyloid fibrils is a critical event in the pathogenesis of Alzheimer's disease (AD). Notably, previous studies have suggested that cross-interactions between amyloid-α protein (Aα) and Aβ could provide a novel therapeutic strategy for AD. However, the physical mechanism of Aα co-assembly with Aβ during the early stage remains elusive due to the fast aggregation speed. Herein, to investigate the effect of Aα on Aβ assembly, we performed molecular dynamics (MD) simulations on Aα/Aβ mixed heterooctamer and Aα/Aβ isolated homooctamer systems. Based on the currently observed patterns of Aα/Aβ mixed heterooctamer, we proposed that the most stable pattern is the (Aα₂Aβ₂)₂ system featuring two chains of Aα adjacent to two chains of Aβ in each layer. Our results demonstrate that Aα induced Aβ to form more β-sheet content in the 17-42 segment. Structural analysis reveals that the intra-layer salt bridge and the inter-layer hydrophobic interactions play crucial roles in the co-assembly process of Aα and Aβ. Our work dissects the Aα/Aβ co-assembly mechanisms at the atomic level, which will contribute to a deeper understanding of the pathogenesis of AD.