Amyloid β accelerates age-related proteome-wide protein insolubility

Amyloid β is a protein that has been identified to have an important role in forming protein components and neurodegeneration in Alzheimer's disease. The proteins that are formed in Alzheimer's disease (AD) are often folded incorrectly, or insoluble, disrupting or inhibiting their function.

A study conducted with several strains of C. elegans aimed to discover whether there is a relationship between Amyloid β (Aβ)brain protein and insoluble proteins related to aging.

A strain of C. elegans that expresses the specific types of Aβ proteins that result in insolubility in humans was used. The authors concluded that Aβ was responsible for insolubility in 593 of the 1704 proteins they tested, in both young and older models. Additionally, heat shock proteins, which act as buffers for other proteins and initiate formation of new ones, increased in number as the amount of insolubility grew. Finally, the authors observed an increase in insolubility on most subunits of RNA and proteins that help translate RNA into new proteins. They also identified building blocks of proteins, or proteomes, that were critical to rendering a protein insoluble, labelled “core insoluble proteome” (CIP).

Of the 593 insoluble proteins, 109 were proteins stored in the mitochondria and expressed far more Aβ insolubility than the remaining proteins. This was specifically true with proteins that are involved in the electron transport chain (ETC) or the Krebbs cycle. The electron transport chain are a series of proteins that remove an extra electron from a donor molecule and give it to a receptor molecule. The Krebbs cycle is a series of reactions that oxidate carbohydrates, fatty acids, and proteins to produce energy. Proteins that are part of the ETC and were produced in the nucleus of a cell were more likely to be insoluble.

The CIP contained the most changes to the programmed lifespan of the protein, which would result in a longer lifespan for the majority of these proteins if their expression were reduced, like would be the case in AD. The elimination of many of these proteins CIPs improved symptoms of Huntington’s and Parkinson’s.

Anderton et. al. concluded that Aβ could possible be the single driver of protein insolubility, in particular in mitochondrial ETC transporter proteins. This insolubility is similar to that in normal aging, and they suggest that the similar proteome may be changed in neurodegenerative diseases due to stress. They observed that insoluble proteomes have many nuclear-encoded, but not mitochondrial-encoded proteins.

Finally, they discovered that Urolithin A (UA), a byproduct of bacterial metabolism of pomegranate seeds and walnuts, could be used to stimulate manufacturing mitochondrial proteins. UA also prevented Aβ insolubility, leading the authors to suggest this as a possible therapy for neurodegeneration.