Department of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu 42988, South Korea.
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 41944, South Korea.
Cell Rep. 2023 Oct 31;42(10):113183. doi: 10.1016/j.celrep.2023.113183. Epub 2023 Sep 29.
Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation.
近年来，基因组测序的发展扩展了与迟发性阿尔茨海默病（AD）相关的遗传因素的知识。其中，载脂蛋白 E 基因（APOE）的遗传变异 ε4（APOE4）赋予了最大的疾病风险。葡萄糖代谢失调是 AD 的早期病理特征。使用源自人诱导多能干细胞的同基因 ApoE3 和 ApoE4 星形胶质细胞，我们发现 ApoE4 增加了星形胶质细胞的糖酵解活性，但损害了线粒体呼吸作用。超微结构和自噬通量分析表明，ApoE4 诱导的胆固醇积累会损害溶酶体依赖性清除受损线粒体。用耗竭胆固醇的试剂进行急性处理可恢复自噬活性、线粒体动力学和相关蛋白质组，延长处理可挽救 ApoE4 星形胶质细胞中的线粒体呼吸作用。综上所述，我们的研究提供了 ApoE4 诱导的溶酶体胆固醇积累与异常氧化磷酸化之间的直接联系。
