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

Overview

Authors: Haitao Yu1,2, Fangzhou Wang1, Jia-qi Yuan1, Jia Chen1, Ke-yu Zhang1, Dongdong Jia3, Juan Gong1, Yuming Mao1, Shuguang Bi1, Yu-qi Zhang1, Zi-chong Lan1, Hao-yan Yu1, Gao-shang Chai1
ORCID iDs: Haitao Yu, Gao-shang Chai
  1. Department of Fundamental Medicine, Wuxi School of Medicine, Jiangnan University; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, Wuxi, People’s Republic of China
  2. Affiliated Hospital of Jiangnan University, Wuxi, People’s Republic of China
  3. The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, People’s Republic of China
Institutions: Jiangnan University (China); Wuxi Fourth People's Hospital (China)
Journal: Experimental & molecular medicine, volume 58, issue 3, pages 813-831
Dates: received 15 April 2025; accepted 30 December 2025; published online 6 March 2026; in print March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s12276-026-01664-9 · PMID 41792234 · PMCID PMC13049083 · OpenAlex W7134032980
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics
Keywords: Histone analysis, Long-term potentiation
MeSH: 3-Hydroxybutyric Acid*, Alzheimer Disease*, Cognition*, Histones*, Hydroxymethylglutaryl-CoA Synthase*, Neuronal Plasticity*, Animals, Disease Models, Animal, Hippocampus, Humans, Male, Mice, Mice, Transgenic, Receptors, N-Methyl-D-Aspartate (* major topic)
Topic: Diet and metabolism studies (Physiology, Medicine), according to OpenAlex
Funding: National Natural Science Foundation of China (National Science Foundation of China) (82505712, 82401671, 81601121); Natural Science Foundation of Jiangsu Province (Jiangsu Provincial Natural Science Foundation) (BK20211238)
Citations: cited by 3 papers (Europe PMC); 41 references in the paper

Abstract

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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All data used to support the findings of this study are included within the Article, and raw data are available from the corresponding author.

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Versions

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 2 keywords, 14 MeSH terms, 2 funders, 38 references.

Cite

This paper

Yu, H., Wang, F., Yuan, J.-q., Chen, J., Zhang, K.-y., Jia, D., Gong, J., Mao, Y., Bi, S., Zhang, Y.-q., Lan, Z.-c., Yu, H.-y., & Chai, G.-s. (2026). HMGCS2-dependent β-OHB/H3K9bhb ameliorates synaptic plasticity and cognition in Alzheimer's disease. Experimental & molecular medicine, 58(3), 813-831. https://doi.org/10.1038/s12276-026-01664-9

BibTeX

@article{yu2026hmgcs2,
author = {Yu, Haitao and Wang, Fangzhou and Yuan, Jia-qi and Chen, Jia and Zhang, Ke-yu and Jia, Dongdong and Gong, Juan and Mao, Yuming and Bi, Shuguang and Zhang, Yu-qi and Lan, Zi-chong and Yu, Hao-yan and Chai, Gao-shang},
title = {{HMGCS2-dependent β-OHB/H3K9bhb ameliorates synaptic plasticity and cognition in Alzheimer's disease}},
journal = {Experimental \& molecular medicine},
year = {2026},
month = mar,
volume = {58},
number = {3},
pages = {813--831},
publisher = {Korean Society for Biochemistry and Molecular Biology},
issn = {1226-3613},
doi = {10.1038/s12276-026-01664-9},
url = {https://doi.org/10.1038/s12276-026-01664-9},
pmid = {41792234},
pmcid = {PMC13049083}
}

RIS

TY - JOUR
AU - Yu, Haitao
AU - Wang, Fangzhou
AU - Yuan, Jia-qi
AU - Chen, Jia
AU - Zhang, Ke-yu
AU - Jia, Dongdong
AU - Gong, Juan
AU - Mao, Yuming
AU - Bi, Shuguang
AU - Zhang, Yu-qi
AU - Lan, Zi-chong
AU - Yu, Hao-yan
AU - Chai, Gao-shang
TI - HMGCS2-dependent β-OHB/H3K9bhb ameliorates synaptic plasticity and cognition in Alzheimer's disease
T2 - Experimental & molecular medicine
J2 - Exp Mol Med
PY - 2026
DA - 2026/03/06
VL - 58
IS - 3
SP - 813
EP - 831
SN - 1226-3613
PB - Korean Society for Biochemistry and Molecular Biology
DO - 10.1038/s12276-026-01664-9
UR - https://doi.org/10.1038/s12276-026-01664-9
LA - en
ER -

CSL-JSON

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