HMGCS2-dependent β-OHB/H3K9bhb ameliorates synaptic plasticity and cognition in Alzheimer's disease - PubMed
5 days ago
- #Alzheimer's disease
- #Ketogenic diet
- #HMGCS2
- Ketogenic diet (KD) improves cognition in Alzheimer's disease (AD), but the mechanism is unclear.
- Histone3-lysine9-β-hydroxybutyrylation (H3K9bhb), induced by β-hydroxybutyrate (β-OHB), may play a role in AD prevention and treatment.
- β-OHB and H3K9bhb levels were reduced in the hippocampus of 3xTg-AD mice and AD patients.
- 3xTg-AD mice showed low H3K9bhb enrichment on NMDA receptor subunits, Syn1, and axon-related genes, along with impaired synaptic plasticity.
- HMGCS2 upregulation rescued synaptic plasticity and cognitive function in 3xTg-AD mice.
- β-OHB replenishment enhanced H3K9bhb, increasing NMDA receptor subunits, Syn1, and cognitive function in an HMGCS2-dependent manner.
- HMGCS2 is a key molecular switch for cognitive impairment, and targeting it or β-OHB replenishment could be a novel AD therapeutic strategy.