Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, NC, USA.
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, NC, USA.
Trends Cell Biol. 2024 Apr;34(4):338-348. doi: 10.1016/j.tcb.2023.09.004. Epub 2023 Oct 5.
Apolipoprotein E (APOE) traffics lipids in the central nervous system. The E4 variant of APOE is a major genetic risk factor for Alzheimer's disease (AD) and a multitude of other neurodegenerative diseases, yet the molecular mechanisms by which APOE4 drives disease are still unclear. A growing collection of studies in iPSC models, knock-in mice, and human postmortem brain tissue have demonstrated that APOE4 expression in astrocytes and microglia is associated with the accumulation of cytoplasmic lipid droplets, defects in endolysosomal trafficking, impaired mitochondrial metabolism, upregulation of innate immune pathways, and a transition into a reactive state. In this review, we collate these developments and suggest testable mechanistic hypotheses that could explain common APOE4 phenotypes.
载脂蛋白 E（APOE）在中枢神经系统中转运脂质。APOE 的 E4 变体是阿尔茨海默病（AD）和许多其他神经退行性疾病的主要遗传风险因素，但 APOE4 导致疾病的分子机制仍不清楚。越来越多的 iPSC 模型、基因敲入小鼠和人类尸检脑组织研究表明，星形胶质细胞和小胶质细胞中 APOE4 的表达与细胞质脂滴的积累、内溶酶体运输缺陷、线粒体代谢受损、先天免疫途径上调以及向反应状态的转变有关。在这篇综述中，我们整理了这些进展，并提出了可测试的机制假设，可以解释常见的 APOE4 表型。
