韩国国立首尔大学Inhee Mook-Jung团队的一项最新研究发现，代谢重塑的崩溃会导致阿尔茨海默症（AD）中的小胶质细胞功能障碍。该研究于2019年9月3日发表于国际一流学术期刊《细胞—代谢》。

通过使用代谢分析，研究人员发现暴露于β-淀粉样蛋白会引发急性小胶质细胞炎症，并伴有从氧化磷酸化到糖酵解的代谢重编程，这依赖于mTOR-HIF-1α途径。然而，一旦被激活，由于能量代谢的广泛缺陷以及随后免疫应答的减少（包括细胞因子分泌和吞噬作用），小胶质细胞达到慢性耐受期。使用全基因组RNA测序和多光子显微镜技术，研究人员进一步确定5XFAD小鼠（AD小鼠模型）中代谢缺陷的小胶质细胞。最后，研究人员发现用重组干扰素-γ处理后的代谢增强逆转了小胶质细胞的糖酵解代谢和炎症功能的缺陷，从而减轻了5XFAD小鼠的AD病理。

总的来说，代谢重编程对于AD中的小胶质细胞功能是至关重要的，并且调节代谢可能是AD的新治疗策略。

据了解，反应性小胶质细胞是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。

附：英文原文

Title: A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer's Disease

Author: Jong-Il Kim, Inhee Mook-Jung, et al

Issue&Volume: Volume 30 Issue 3

Abstract: Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using metabolic profiling, we found that exposure to amyloid-β triggers acute microglial inflammation accompanied by metabolic reprogramming from oxidative phosphorylation to glycolysis. It was dependent on the mTOR-HIF-1α pathway. However, once activated, microglia reached a chronic tolerant phase as a result of broad defects in energy metabolisms and subsequently diminished immune responses, including cytokine secretion and phagocytosis. Using genome-wide RNA sequencing and multiphoton microscopy techniques, we further identified metabolically defective microglia in 5XFAD mice, an AD mouse model. Finally, we showed that metabolic boosting with recombinant interferon-γ treatment reversed the defective glycolytic metabolism and inflammatory functions of microglia, thereby mitigating the AD pathology of 5XFAD mice. Collectively, metabolic reprogramming is crucial for microglial functions in AD, and modulating metabolism might be a new therapeutic strategy for AD.

DOI: https://doi.org/10.1016/j.cmet.2019.06.005

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30308-0#