Interactions between Soluble Species of β-Amyloid and α-Synuclein Promote Oligomerization while Inhibiting Fibrillization

Aggregations of beta-amyloid (A beta) and alpha-synuclein (alpha S) into oligomeric and fibrillar assemblies are the pathological hallmarks of Alzheimer's and Parkinson's diseases, respectively. Although A beta and alpha S affect different regions of the brain and are separated at the cellular level, there is evidence of their eventual interaction in the pathology of both disorders. Characterization of interactions of A beta and alpha S at various stages of their aggregation pathways could reveal mechanisms and therapeutic targets for the prevention and cure of these neurodegenerative diseases. In this study, we comprehensively examined the interactions and their molecular manifestations using an array of characterization tools. We show for the first time that alpha S monomers and oligomers, but not alpha S fibrils, inhibit A beta fibrillization while promoting oligomerization of A beta monomers and stabilizing preformed A beta oligomers via coassembly, as judged by Thioflavin T fluorescence, transmission electron microscopy, and SDS- and native-PAGE with fluorescently labeled peptides/proteins. In contrast, soluble A beta species, such as monomers and oligomers, aggregate into fibrils, when incubated alone under the otherwise same condition. Our study provides evidence that the interactions with alpha S soluble species, responsible for the effects, are mediated primarily by the C-terminus of A beta, when judged by competitive immunoassays using antibodies recognizing various fragments of A beta. We also show that the C-terminus of A beta is a primary site for its interaction with alpha S fibrils. Collectively, these data demonstrate aggregation state-specific interactions between alpha S and A beta and offer insight into a molecular basis of synergistic biological effects between the two polypeptides.