期刊
CELL METABOLISM
卷 34, 期 4, 页码 634-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2022.02.013
关键词
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资金
- National Natural Science Foundation of China [81930029, 81630026, 81874158, 82002992]
- Ministry of Science and Technology of China [2021YFA1300603]
- NFSC-Henan Joint Funding [U2004201]
- National Major Project of Support Program [2019-JCJQ-ZD-195]
- National Program for Support of Top-notch Young Professionals [QNBJ2020-2]
- Beijing Natural Science Foundation [7161009, Z200020]
- China Postdoctoral Science Foundation [2020M683748, 2019M650385]
- Open Project of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine [TCM-201914]
The dysregulation of microglial function in Alzheimer's disease is associated with the glycolysis/H4K12la/PKM2 positive feedback loop. Inhibiting this loop can ameliorate pathological changes and cognitive deficits in a mouse model. This suggests that disrupting the positive feedback loop may be a potential therapeutic approach for treating AD.
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 A beta 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 A beta 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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