The Ketone Body β-hydroxybutyrate is Involved in Clearance of Amyloid-β
Researchers here note an interesting role for one of the common ketone bodies found in mammalian biochemistry, in that it provokes clearance of amyloid-β via its interaction with that molecule. An increase in misfolded amyloid-β is involved in the early stages of Alzheimer's disease, and seems likely to cause some fraction of the pathology of that condition. If comparatively simple approaches could keep amyloid-β levels low in later life, then the incidence of Alzheimer's disease might be reduced. That said, while the mechanism described here is interesting, it doesn't mean that the effect size, relative to other mechanisms involved in Alzheimer's disease, will actually turn out to be large enough to care about. Finding out whether that is the case will require further efforts.
Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). Here, we identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility in the aging brain. βHB is a small molecule metabolite which primarily provides an oxidative substrate for ATP during hypoglycemic conditions, and also regulates other cellular processes through covalent and noncovalent protein interactions.
We demonstrate βHB-induced protein insolubility across in vitro, ex vivo, and in vivo mouse systems. This βHB-induced insolubility leads to misfolded protein turnover in vivo, likely via βHB communication with cellular protein degradation pathways. This activity is shared by select structurally similar metabolites, and is observable in mouse brains in vivo after delivery of a ketone ester. Furthermore, this phenotype is selective for pathological proteins such as amyloid-β, and delivery of exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity.
We have generated a comprehensive atlas of the βHB-induced protein insolubility using mass spectrometry proteomics, and have identified common protein domains within βHB target sequences. Finally, we show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain, likely via βHB-induced autophagy. Overall, these data indicate a new metabolically regulated mechanism of proteostasis relevant to aging and AD.