ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes
Hyein Lee,
Sukhee Cho,
Mi-Jin Kim,
Yeo Jin Park,
Eunji Cho,
Yeon Suk Jo,
Yong-Seok Kim,
Jung Yi Lee,
Themis Thoudam,
Seung-Hwa Woo,
Se-In Lee,
Juyeong Jeon,
Young-Sam Lee,
Byung-Chang Suh,
Jong Hyuk Yoon,
Younghoon Go,
In-Kyu Lee,
Jinsoo Seo
Affiliations
Hyein Lee
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu 42988, South Korea
Sukhee Cho
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu 42988, South Korea
Mi-Jin Kim
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 41944, South Korea
Yeo Jin Park
Korean Medicine Life Science, University of Science and Technology, Daejeon 34054, South Korea; Korean Medicine-Application Center, Korea Institute of Oriental Medicine, Daegu 41062, South Korea
Eunji Cho
Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu 41062, South Korea
Yeon Suk Jo
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu 42988, South Korea; Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu 41062, South Korea
Yong-Seok Kim
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu 42988, South Korea
Jung Yi Lee
Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University School of Medicine, Daegu 41944, South Korea
Themis Thoudam
Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu 41944, South Korea
Seung-Hwa Woo
Department of New Biology, Daegu Gyeongbuk Institute of Science & Technology, Daegu 42988, South Korea
Se-In Lee
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu 42988, South Korea
Juyeong Jeon
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu 42988, South Korea
Young-Sam Lee
Department of New Biology, Daegu Gyeongbuk Institute of Science & Technology, Daegu 42988, South Korea
Byung-Chang Suh
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu 42988, South Korea
Jong Hyuk Yoon
Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu 41062, South Korea
Younghoon Go
Korean Medicine-Application Center, Korea Institute of Oriental Medicine, Daegu 41062, South Korea; Corresponding author
In-Kyu Lee
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 41944, South Korea; Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University School of Medicine, Daegu 41944, South Korea; Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu 41944, South Korea; Corresponding author
Jinsoo Seo
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu 42988, South Korea; Corresponding author
Summary: 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.
