HMGCS2-dependent β-OHB/H3K9bhb ameliorates synaptic plasticity and cognition in Alzheimer’s disease

Ketogenic diet (KD) can significantly ameliorate cognition in Alzheimer's disease (AD), but the specific mechanism is not clear. Histone3-lysine9-β-hydroxybutyrylation (H3k9bhb), a novel histone modification mark induced by ketogenesis-generated β-hydroxybutyrate (β-OHB), may be involved in the prevention and treatment of AD. Here we report that β-OHB and H3K9bhb were reduced in the hippocampus of triple transgenic AD male mice (3xTg-AD) mice. Reduced H3K9bhb levels were also observed in patients with AD. The 3xTg-AD mice exhibited a low enrichment of H3K9bhb on the promoters of NMDA receptor subunits and Syn1 and axon-related genes together with impaired synaptic plasticity, all of which were rescued by 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2, a rate-limiting enzyme of β-OHB synthesis) upregulation. Moreover, β-OHB replenishment enhanced H3K9bhb in 3xTg-AD mice, leading to an increase of NMDA receptor subunits and Syn1 and cognitive function in an HMGCS2-dependent manner. Thus, HMGCS2 is a key molecular switch of cognitive impairment, and targeting HMGCS2 or β-OHB replenishment appropriately may serve as a novel therapeutic strategy for AD treatment.