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

Abstract

Aggregations of β-amyloid (Aβ) and α-synuclein (αS) into oligomeric and fibrillar assemblies are the pathological hallmarks of Alzheimer's and Parkinson's diseases, respectively. Although Aβ and αS 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 Aβ and αS 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 αS monomers and oligomers, but not αS fibrils, inhibit Aβ fibrillization while promoting oligomerization of Aβ monomers and stabilizing preformed Aβ oligomers via co-assembly, as judged by Thioflavin T fluorescence, transmission electron microscopy and SDS-and native-PAGE with fluorescently labeled peptides/proteins. In contrast, soluble Aβ 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 αS soluble species, responsible for the effects, are mediated primarily by the Cterminus of Aβ, when judged by competitive immunoassays using antibodies recognizing various fragments of Aβ. We also show that the C-terminus of Aβ is a primary site for its interaction with αS fibrils. Collectively, these data demonstrate aggregation state-specific interactions between αS and Aβ, and offer insight into a molecular basis of synergistic biological effects between the two polypeptides.

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

“…While structural information for the Aβ oligomers induced by αS has still not been reported, further investigation could provide more details to establish a correlation between AD and PD. 297 The aggregation and folding of αS is shown to be modulated by the isomeric state of the five proline residues (P108, P117, P120, P128, and P138) located in the disordered C-terminus. 298 Among the five-proline residues, isomerization of P128 is identified to be catalyzed by cyclophilin A (CypA), a protein belonging to the family of peptidylprolyl isomerases.…”

Collusion of α-Synuclein and Aβ aggravating co-morbidities in a novel prion-type mouse model

“…As αSyn was initially described as the non-amyloid component of amyloid plaques (NACP) [77], the direct interactions and copolymerization of αSyn and Aβ have been reported in many in vitro studies [67,[78][79][80][81][82][83]. In fact, PFFs have been shown to be able to nucleate Aβ aggregation [84]; however the literature on this topic is complicated.…”

“…In fact, PFFs have been shown to be able to nucleate Aβ aggregation [84]; however the literature on this topic is complicated. In 2020, Candreva et al, demonstrated that αSyn monomers and oligomers co-assemble with Aβ, stabilizing Aβ oligomers and thus preventing Aβ fibrillization, whereas αSyn fibrils did not change fibrillization [83]. Furthermore, the effect of αSyn on Aβ fibrilization was lost when aggregation studies were seeded with preformed Aβ fibrils [83].…”

“…In 2020, Candreva et al, demonstrated that αSyn monomers and oligomers co-assemble with Aβ, stabilizing Aβ oligomers and thus preventing Aβ fibrillization, whereas αSyn fibrils did not change fibrillization [83]. Furthermore, the effect of αSyn on Aβ fibrilization was lost when aggregation studies were seeded with preformed Aβ fibrils [83]. Taken together, these results hint towards a possible sequence-dependent phenomenon, where progression of pathology depends on which protein first began forming pathological inclusions.…”

α-Synuclein Aggregation is Triggered by Amyloid-β Oligomers via Heterogeneous Primary Nucleation

“…Recently, it has been found that α-syn can either accelerate or inhibit the aggregation of Aβ. This dual mechanism of α-syn has been observed on both the 40-residue-long (Aβ40) and the 42-residue-long (Aβ42) isoforms of Aβ (22,(34)(35)(36)(37)(38). Whether α-syn promotes or inhibits Aβ aggregation seems to depend on the aggregated state of α-syn.…”