Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease
Open accessAbstract
The pro-inflammatory activation of microglia is a hallmark of Alzheimer's disease (AD), and this process involves a switch from oxidative phosphorylation (OXPHOS) toward glycolysis. Here, we show how a positive feedback loop in microglia drives AD pathogenesis, and we demonstrate that inhibiting this cycle in microglia can ameliorate Aβ burden and cognitive deficits in an AD mouse model (5XFAD). After first detecting elevated histone lactylation in brain samples from both 5XFAD mice and individuals with AD, we observed that H4K12la levels are elevated in Aβ plaque-adjacent microglia. This lactate-dependent histone modification is enriched at the promoters of glycolytic genes and activates transcription, thereby increasing glycolytic activity. Ultimately, the glycolysis/H4K12la/PKM2 positive feedback loop exacerbates microglial dysfunction in AD. Pharmacologic inhibition of PKM2 attenuated microglial activation, and microglia-specific ablation of Pkm2 improved spatial learning and memory in AD mice. Thus, our study illustrates that disruption of the positive feedback loop may be a potential therapeutic approach for the treatment of AD.
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Lactate-dependent histone lactylation (H4K12a) in microglia promotes the expression of glycolytic genes, leading to microglial dysfunction and cognitive decline.
“Lactate-dependent histone lactylation (H4K12a) in microglia promotes the expression of glycolytic genes, leading to microglial dysfunction and cognitive decline.420”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [420]
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- Authors
- Pan, R.-Y., He, L., Zhang, J., Liu, X., Liao, Y., Gao, J., Liao, Y., Yan, Y., Li, Q., Zhou, X., Cheng, J., Xing, Q., Guan, F., Zhang, J., Sun, L., & Yuan, Z.
- Affiliations
- Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences (CN)
- Peking University (CN)
- Xiamen University (CN)
- Hangzhou Normal University (CN)
- Jiangxi University of Traditional Chinese Medicine (CN)
- University of Nebraska Medical Center (US)
- Minzu University of China (CN)
- Zhengzhou University (CN)
- Corresponding author
- Sun, Luyang
- Yuan, Zengqiang
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2022-04
- Volume
- 34
- Issue
- 4
- Pages
- 634-648.e6
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W4220860947
- Cited by
- 862
- References
- 62
- Citations by year
- 2026: 239 · 2025: 285 · 2024: 210 · 2023: 88 · 2022: 39
- FWCI
- 55.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 369 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- SSRN Electronic Journal (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81930029, 81630026, 82002992, 81874158)
- National Program for Support of Top-notch Young Professionals (QNBJ2020-2)
- Natural Science Foundation of Beijing Municipality (7161009, Z200020)
- China Postdoctoral Science Foundation (2020M683748, 2019M650385)
- Ministry of Science and Technology of the People's Republic of China (2021YFA1300603)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, microglia, glycolysis, oxidative phosphorylation, PKM2, positive feedback loop, amyloid-beta, 5xFAD mice, microglial activation, spatial learning and memory, histone modifications
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Glucose, Histones, Lysine, Mice, Transgenic, Amyloid beta-Peptides, Microglia, Feedback, Physiological, Mice
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