Aβ42 promotes the aggregation of α‐synuclein splice isoforms <i>via</i> heterogeneous nucleation

Increasing evidence suggests that amyloid-β (Aβ) and α-synuclein (αSyn) co-aggregate in Alzheimer's disease (AD) and Parkinson's disease (PD), an in other neurodegenerative disorders. We investigated how Aβ42 - the predominant Aβ form in AD - co-aggregates with four αSyn splice isoforms (αSyn-140, αSyn-126, αSyn-112 and αSyn-98) implicated in PD, finding evidence of a two-step process. Aβ42 first aggregated into fibrillar assemblies, which then acted as potent nucleation surfaces for initiating the aggregation of αSyn isoforms. Furthermore, pre-formed Aβ42 seeds promoted αSyn aggregation more strongly than in situ Aβ42 aggregates. Our results reveal a unified Aβ-αSyn co-aggregation mechanism, where Aβ aggregation and αSyn splicing synergistically drive co-deposition. These findings could help develop therapeutic tools to target key steps in disease-related co-aggregation pathways. Impact statement By demonstrating that Aβ42 fibril seeds serve as potent heterogeneous nucleation surfaces for four common α-synuclein splice isoforms, this study mechanistically links protein aggregation in Alzheimer's and Parkinson's diseases. Kinetic analysis identifies early cross-seeding events, suggesting intervention points to delay mixed amyloid pathologies in neurodegeneration.