Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance
Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance
复制标题
小胶质细胞己糖激酶 2 缺乏通过脂质代谢增加 ATP 生成，导致 β-淀粉样蛋白清除
DOI：
10.1038/s42255-022-00643-4
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发表时间：
2022-10-06
影响因子：
20.8
通讯作者：
Zhang, Jie
中科院分区：
文献类型：
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作者：
Leng, Lige;Yuan, Ziqi;Zhang, Jie
小胶质细胞在吞噬作用期间消耗三磷酸腺苷（ATP）以清除阿尔茨海默病（AD）中的神经毒性β-淀粉样蛋白。然而，在AD中能量代谢对小胶质细胞功能的贡献仍不清楚。在这里，我们证明了己糖激酶2（HK 2）在AD小鼠模型（5xFAD）和AD患者的小胶质细胞中升高。HK 2的遗传缺失或药理学抑制显著促进小胶质细胞吞噬作用，降低淀粉样蛋白斑块负荷并减轻雄性AD小鼠的认知障碍。值得注意的是，ATP水平显着增加HK 2缺陷或无活性的小胶质细胞，这可以归因于脂蛋白脂肪酶（LPL）表达的显着上调和随后的脂质代谢的增加。我们进一步表明，HK 2的两个下游代谢产物，葡萄糖-6-磷酸和果糖-6-磷酸，可以逆转HK 2缺陷诱导的LPL上调，从而支持ATP的产生和小胶质细胞的吞噬作用。我们的研究结果揭示了HK 2通过调节小胶质细胞能量代谢在吞噬中的关键作用，这表明通过靶向HK 2治疗AD的潜在治疗策略。
Microglial cells consume adenosine triphosphate (ATP) during phagocytosis to clear neurotoxic beta-amyloid in Alzheimer's disease (AD). However, the contribution of energy metabolism to microglial function in AD remains unclear. Here, we demonstrate that hexokinase 2 (HK2) is elevated in microglia from an AD mouse model (5xFAD) and AD patients. Genetic deletion or pharmacological inhibition of HK2 significantly promotes microglial phagocytosis, lowers the amyloid plaque burden and attenuates cognitive impairment in male AD mice. Notably, the ATP level is dramatically increased in HK2-deficient or inactive microglia, which can be attributed to a marked upregulation in lipoprotein lipase (LPL) expression and subsequent increase in lipid metabolism. We further show that two downstream metabolites of HK2, glucose-6-phosphate and fructose-6-phosphate, can reverse HK2-deficiency-induced upregulation of LPL, thus supporting ATP production and microglial phagocytosis. Our findings uncover a crucial role for HK2 in phagocytosis through regulation of microglial energy metabolism, suggesting a potential therapeutic strategy for AD by targeting HK2.