Aβ42 promotes the aggregation of α‐synuclein splice isoforms via heterogeneous nucleation

TL;DR

The study shows how amyloid-beta (Aβ42) helps α-synuclein (αSyn) proteins clump together, linking Alzheimer's and Parkinson's disease protein aggregation.

Contribution

The study reveals a two-step co-aggregation mechanism where Aβ42 acts as a nucleation surface for αSyn isoforms.

Findings

Aβ42 aggregates first and then act as nucleation surfaces for αSyn isoforms.

Pre-formed Aβ42 seeds are more effective at promoting αSyn aggregation than in situ aggregates.

The findings suggest potential therapeutic targets for delaying mixed amyloid pathologies.

Abstract

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 statementBy 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.

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.

The aggregation of amyloid‐β (Aβ) and α‐synuclein (αSyn) is associated with Alzheimer's and Parkinson's diseases. This study reveals that Aβ aggregates serve as potent nucleation sites for the aggregation of αSyn and its splice isoforms, shedding light on the intricate interplay between these two pathogenic proteins.

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