TRPV1 sustains microglial metabolic reprogramming in Alzheimer's disease
TRPV1 sustains microglial metabolic reprogramming in Alzheimer's disease
复制标题
TRPV1 维持阿尔茨海默病中小胶质细胞代谢重编程
DOI：
10.15252/embr.202052013
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发表时间：
2021-05-17
期刊：
影响因子：
7.7
通讯作者：
Yu, Zhihua
中科院分区：
文献类型：
--
作者：
Lu, Jia;Zhou, Wei;Yu, Zhihua
反应性小胶质细胞作为脑内固有免疫细胞，是阿尔茨海默病（AD）的主要病理特征。然而，小胶质细胞在AD发病机制中的确切作用仍不清楚。在这里，使用代谢分析，我们表明，小胶质细胞的能量代谢显着抑制慢性A β耐受过程中，包括氧化磷酸化和有氧糖酵解通过mTOR-AKT-HIF-1 α途径。TRPV 1的药理学激活挽救了A β耐受性小胶质细胞功能障碍、AKT/mTOR通路活性和代谢损伤，并恢复了免疫应答，包括吞噬活性和自噬功能。在小胶质细胞特异性TRPV 1敲除APP/PS1小鼠中，淀粉样蛋白病理学和记忆障碍加速。最后，我们发现，用TRPV 1激动剂的代谢增强减少了AD小鼠模型中的淀粉样蛋白病理学并逆转了记忆缺陷。这些结果表明，TRPV 1是AD治疗中调节小胶质细胞功能代谢重编程的重要靶标。
As the brain-resident innate immune cells, reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia is still unclear in AD pathogenesis. Here, using metabolic profiling, we show that microglia energy metabolism is significantly suppressed during chronic A beta-tolerant processes including oxidative phosphorylation and aerobic glycolysis via the mTOR-AKT-HIF-1 alpha pathway. Pharmacological activation of TRPV1 rescues A beta-tolerant microglial dysfunction, the AKT/mTOR pathway activity, and metabolic impairments and restores the immune responses including phagocytic activity and autophagy function. Amyloid pathology and memory impairment are accelerated in microglia-specific TRPV1-knockout APP/PS1 mice. Finally, we showed that metabolic boosting with TRPV1 agonist decreases amyloid pathology and reverses memory deficits in AD mice model. These results indicate that TRPV1 is an important target regulating metabolic reprogramming for microglial functions in AD treatment.