The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
Department of Biochemistry and Molecular Biology, Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing 100191, China.
Cell Metab. 2022 Apr 5;34(4):634-648.e6. doi: 10.1016/j.cmet.2022.02.013. Epub 2022 Mar 17.
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.
小胶质细胞的促炎激活是阿尔茨海默病（AD）的标志，这一过程涉及从氧化磷酸化（OXPHOS）向糖酵解的转变。在这里，我们展示了小胶质细胞中的正反馈环如何驱动 AD 的发病机制，并证明抑制小胶质细胞中的这个循环可以改善 AD 小鼠模型（5XFAD）中的 Aβ负担和认知缺陷。在首次检测到 5XFAD 小鼠和 AD 患者的大脑样本中组蛋白乳酰化水平升高后，我们观察到 Aβ斑块附近的小胶质细胞中 H4K12la 水平升高。这种依赖于乳酸的组蛋白修饰在糖酵解基因的启动子处富集，并激活转录，从而增加糖酵解活性。最终，糖酵解/H4K12la/PKM2 正反馈环加剧了 AD 中小胶质细胞的功能障碍。PKM2 的药理学抑制减弱了小胶质细胞的激活，而 AD 小鼠中小胶质细胞特异性敲除 Pkm2 则改善了空间学习和记忆。因此，我们的研究表明，破坏正反馈环可能是治疗 AD 的一种潜在治疗方法。
