美国加州大学Chen Xu研究小组近日取得一项新成果。经过不懈努力，他们的研究发现Tau病理脑中小胶质细胞脂质液滴聚集受神经元AMPK调控。2024年4月23日出版的《细胞—代谢》杂志发表了这项成果。

利用受激拉曼散射(SRS)显微镜，课题组人员观察到脂质液滴（LD）在tau病理性脑的小胶质细胞中有明显的原位积累。SRS成像，结合氧化氘(D2O)标记，揭示了tau病理果蝇大脑和来自诱导多能干细胞(iPSCs)人类神经元中的脂质生成增加和脂质转换受损。不饱和脂质从tau病理性iPSC神经元转移到小胶质细胞诱导脂质液滴积累、氧化应激、炎症和吞噬功能受损。

神经元AMP活化蛋白激酶(AMPK)抑制脂肪生成并促进神经元的脂质吞噬，从而减少脂质向小胶质细胞的流动。早期tau病变小鼠中AMPK的缺失增加了液滴的积累，加剧了促炎性小胶质细胞增生，并促进了神经病理学。他们的发现提供了直接的证据，证明了先天性的、异常的脂质液滴在tau病变大脑中积累，并强调了AMPK在调节脑脂质稳态中的关键作用。

脂质液滴(LDs)在衰老和阿尔茨海默病大脑中的积累被认为是一种病理现象，其细胞和分子机制尚未解决。

附：英文原文

Title: Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK

Author: Yajuan Li, Daniel Munoz-Mayorga, Yuhang Nie, Ningxin Kang, Yuren Tao, Jessica Lagerwall, Carla Pernaci, Genevieve Curtin, Nicole G. Coufal, Jerome Mertens, Lingyan Shi, Xu Chen

Issue&Volume: 2024-04-23

Abstract: The accumulation of lipid droplets (LDs) in aging and Alzheimer’s disease brains isconsidered a pathological phenomenon with unresolved cellular and molecular mechanisms.Utilizing stimulated Raman scattering (SRS) microscopy, we observed significant in situ LD accumulation in microglia of tauopathy mouse brains. SRS imaging, combined withdeuterium oxide (D2O) labeling, revealed heightened lipogenesis and impaired lipid turnover within LDsin tauopathy fly brains and human neurons derived from induced pluripotent stem cells(iPSCs). Transfer of unsaturated lipids from tauopathy iPSC neurons to microglia inducedLD accumulation, oxidative stress, inflammation, and impaired phagocytosis. NeuronalAMP-activated protein kinase (AMPK) inhibits lipogenesis and promotes lipophagy inneurons, thereby reducing lipid flux to microglia. AMPK depletion in prodromal tauopathymice increased LD accumulation, exacerbated pro-inflammatory microgliosis, and promotedneuropathology. Our findings provide direct evidence of native, aberrant LD accumulationin tauopathy brains and underscore the critical role of AMPK in regulating brain lipidhomeostasis.

DOI: 10.1016/j.cmet.2024.03.014

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00118-9