α-synuclein-assisted oligomerization of β-amyloid (1–42)

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders, characterized by aggregation of amyloid polypeptides, β-amyloid (Aβ) and α-synuclein (αS), respectively. Aβ and αS follow similar aggregation pathways, starting from monomers, to soluble toxic oligomeric assemblies, and to insoluble fibrils. Various studies have suggested overlaps in the pathologies of AD and PD, and have shown Aβ-αS interactions. Unfortunately, whether these protein-protein interactions lead to self- and co-assembly of Aβ and αS into oligomers – a potentially toxic synergistic mechanism – is poorly understood. Among the various Aβ isoforms, interactions of Aβ containing 42 amino acids (Aβ (1–42), referred to as Aβ42) with αS are of most direct relevance due to the high aggregation propensity and the strong toxic effect of this Aβ isoform. In this study, we carefully determined molecular consequences of interactions between Aβ42 and αS in their respective monomeric, oligomeric, and fibrillar forms using a comprehensive set of experimental tools. We show that the three αS conformers, namely, monomers, oligomers and fibrils interfered with fibrillization of Aβ42. Specifically, αS monomers and oligomers promoted oligomerization and stabilization of soluble Aβ42, possibly via direct binding or co-assembly, while αS fibrils hindered soluble Aβ42 species from converting into insoluble aggregates by the formation of large oligomers. We also provide evidence that the interactions with αS were mediated by various parts of Aβ42, depending on Aβ42 and αS conformers. Furthermore, we compared similarities and dissimilarities between Aβ42-αS and Aβ40-αS interactions. Overall, the present study provides a comprehensive depiction of the molecular interplay between Aβ42 and αS, providing insight into its synergistic toxic mechanism.