Does Amyloid-β Aggregation Cause Broad Disruption of Proteostasis?

Researchers here speculate on the ability of insoluble amyloid-β aggregates to be broadly disruptive of the solubility of many other proteins, and thus disruptive to cell and tissue function. Is this important in aging? The evidence here shows the existence of the mechanism in a lower species, but that doesn't necessarily show that it has a sizable effect in mammals. Still, it is an interesting concept, potentially linking everything we know about why amyloid-β increases with age to the observed general dysfunction of brain cells.

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, providing suggestive evidence that age-related loss of proteostasis could play a role in general age-related disease risk.

Link: https://doi.org/10.1101/2023.07.13.548937

Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.