Amyloid β accelerates age-related proteome-wide protein insolubility.

Loss of proteostasis is a highly conserved feature of aging across model organisms and typically results in the accumulation of insoluble protein aggregates. Protein insolubility is a central feature of major age-related neurodegenerative diseases including Alzheimer’s Disease (AD), where hundreds of insoluble proteins associate with aggregated amyloid beta (Aβ) in senile plaques. Despite the established connection between aging and AD risk, therapeutic approaches to date have overlooked aging and proteome-wide protein insolubility as causal factors, instead focusing on Aβ and Tau. Here, using an unbiased proteomics approach, we questioned the relationship between Aβ and age-related protein insolubility. We demonstrate that, in C. elegans, Aβ expression is sufficient to drive proteome-wide protein insolubility. The Aβ-driven insoluble proteome bears a highly significant overlap with the aging-driven insoluble proteome, suggesting there exists a core, sub-proteome which is vulnerable to insolubility. Using human genome-wide association studies (GWAS) we show that this insoluble sub proteome is replete with biological processes implicated across not only neurodegenerative diseases but also across a broad array of chronic, age-related diseases (CARDs), providing suggestive evidence that age-related loss of proteostasis could play a role in general CARD risk. Finally, we show that the gut metabolite, Urolithin A, relieves Aβ toxicity supporting its use in clinical trials for dementia and other age-related diseases.