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bioRxiv · 10.1101/2023.07.13.548937

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

Anderton, E.·Chamoli, M.·Bhaumik, D.·King, C. D.·Xie, X.·Foulger, A.·Andersen, J.·Schilling, B.·Lithgow, G.
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Abstract

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 Alzheimers Disease (AD), where hundreds of insoluble proteins associate with aggregated amyloid beta (A{beta}) in senile plaques. Moreover, proteins that become insoluble during aging in model organisms are capable of accelerating A{beta} aggregation in vitro. Despite the connection between aging and AD risk, therapeutic approaches to date have overlooked aging-driven protein insolubility as a contributory factor. Here, using an unbiased proteomics approach, we questioned the relationship between A{beta} and age-related protein insolubility. We demonstrate that A{beta} expression drives proteome-wide protein insolubility in C. elegans and this insoluble proteome closely resembles the insoluble proteome driven by normal aging, suggesting the possibility of a vicious feedforward cycle of aggregation in the context of AD. Importantly, using human genome-wide association studies (GWAS), we show that the CIP is replete with biological processes implicated not only in neurodegenerative diseases but also across a broad array of chronic, age-related diseases (CARDs). This provides suggestive evidence that age-related loss of proteostasis could play a role in general CARD risk. Finally, we show that the CIP is enriched with proteins that modulate the toxic effects of A{beta} and that the gut-derived metabolite, Urolithin A, relieves A{beta} toxicity, supporting its use in clinical trials for dementia and other age-related diseases.

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Anderton, E., Chamoli, M., Bhaumik, D., King, C. D., Xie, X., Foulger, A., Andersen, J., Schilling, B., Lithgow, G.. 2023-07-15. Amyloid β accelerates age-related proteome-wide protein insolubility.. https://doi.org/10.1101/2023.07.13.548937

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