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Histone3-lysine9-\u03b2-hydroxybutyrylation (H3k9bhb), a novel histone modification mark induced by ketogenesis-generated \u03b2-hydroxybutyrate (\u03b2-OHB), may be involved in the prevention and treatment of AD. Here we report that \u03b2-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 \u03b2-OHB synthesis) upregulation. Moreover, \u03b2-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 \u03b2-OHB replenishment appropriately may serve as a novel therapeutic strategy for AD treatment.<\/jats:p>","DOI":"10.1038\/s12276-026-01664-9","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T09:18:48Z","timestamp":1772788728000},"page":"813-831","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["HMGCS2-dependent \u03b2-OHB\/H3K9bhb ameliorates synaptic plasticity and cognition in Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0302-998X","authenticated-orcid":false,"given":"Haitao","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangzhou","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-qi","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke-yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongdong","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuming","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuguang","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-qi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-chong","family":"Lan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-yan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1943-3717","authenticated-orcid":false,"given":"Gao-shang","family":"Chai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"1664_CR1","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/S1474-4422(18)30499-X","volume":"18","author":"GBDN Collaborators","year":"2019","unstructured":"Collaborators, G. 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All experiments conducted with these mice adhere to the ethical considerations and animals\u2019 well-being [12]. Human brain tissue samples were approved by the ethics committee of Guizhou Medical University and ethics committee of Jiangnan University (no. JNU202403RB095).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}