β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain, 2024, Madhavan, et al

"Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. This mechanism is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We generate libraries of the βHB-induced protein insolublome using mass spectrometry proteomics, and identify common protein domains and upstream regulators. We show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain. These data indicate a metabolically regulated mechanism of proteostasis relevant to aging and AD."

https://www.cell.com/cell-chemical-...m/retrieve/pii/S2451945624004598?showall=true

 

"Key Facts

Ketone bodies directly bind to misfolded proteins, enhancing their clearance via autophagy.
Mice treated with ketone esters displayed reduced aggregation of insoluble brain proteins.
Similar metabolites tested showed effects equal to or better than β-hydroxybutyrate."

https://neurosciencenews.com/ketone-bodies-autophagy-28154/