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

Abstract

Neurodegenerative diseases are associated with the formation of amyloids in the nervous system. An increasing number of cases where amyloids of the same protein are found in different dementias is being reported. This observation complicates diagnosis and clinical intervention. Amyloids of the amyloid-β peptide or the protein α-synuclein are traditionally considered hallmarks of Alzheimer's and Parkinson's diseases, respectively. However, the co-occurrence of amyloids of these proteins has also been reported in patients diagnosed with either disease. Here, we provide new evidence about the protein composition of aggregates formed when these two proteins are co-present. We show that soluble species of amyloid-β can induce the aggregation of α-synuclein. The amyloid fibrils formed under these conditions are solely composed of α-synuclein to which amyloid-β can be found associated, but not as part of the core of the fibrils. Our data take us one step closer to understanding the complex nature of heterogenous aggregation in disease contexts which may aid clinical diagnosis and the development of therapeutic interventions.