Metabolic Syndrome, Psychiatric Disorders, Neurology

β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain

Background

Aging and neurodegenerative diseases, such as Alzheimer’s disease (AD), are characterized by the accumulation of misfolded and insoluble proteins.

This study investigated the role of the ketone body β-hydroxybutyrate (BHB) as a metabolic regulator of protein homeostasis (i.e. proteostasis) and its ability to promote the clearance of pathological proteins in the brain.

Methods

The research included in vitro, in vivo (mice), and nematode models, and included proteomic analysis and mass spectrometry to identify proteins affected by BHB. Mice were administered a ketone ester to elevate BHB levels and assess its impact on protein solubility and clearance in the brain.

Key Findings

• BHB promoted protein clearance: BHB selectively induced the insolubility and clearance of pathogenic proteins, such as amyloid-β, a hallmark of Alzheimer’s disease.
• Mechanism independent of chemical modification: BHB-driven protein insolubilization was not due to covalent protein modification, pH changes, or solute load, suggesting a direct metabolic effect.
• Validation in animal models:
  • In mice, BHB administration via a ketone ester reduced neurodegeneration-related proteins in the brain.
  • In C. elegans models of amyloid-β aggregation, BHB reduced proteotoxicity, improving cellular function.

• Metabolic link to proteostasis: BHB’s effect on protein clearance paralleled natural mechanisms induced by fasting, such as autophagy, suggesting that ketone bodies may act as metabolic regulators of protein homeostasis.
• Therapeutic potential: These findings highlight BHB’s therapeutic potential for neurodegenerative diseases, where pathological protein accumulation contributes to disease progression.

Conclusion

This study identifies a previously unknown role of BHB in regulating protein homeostasis in the brain, demonstrating its ability to clear misfolded proteins linked to aging and Alzheimer’s disease. By leveraging ketone metabolism, BHB-based interventions could provide a novel therapeutic approach for neurodegenerative diseases.