APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia

• 成果类型: Article
• 署名作者: Haney, Michael S.; Palovics, Robert; Munson, Christy Nicole; Long, Chris; Johansson, Patrik K.; Yip, Oscar; Dong, Wentao; Rawat, Eshaan; West, Elizabeth; Schlachetzki, Johannes C. M.; Tsai, Andy; Guldner, Ian Hunter; Lamichhane, Bhawika S.; Smith, Amanda; Schaum, Nicholas; Calcuttawala, Kruti; Shin, Andrew; Wang, Yung-Hua; Wang, Chengzhong; Koutsodendris, Nicole; Serrano, Geidy E.; Beach, Thomas G.; Reiman, Eric M.; Glass, Christopher K.; Abu-Remaileh, Monther; Enejder, Annika; Huang, Yadong; Wyss-Coray, Tony
• 署名单位: Stanford University; Stanford University; Stanford University; University of California System; University of California San Francisco; The J David Gladstone Institutes; Stanford University; University of California System; University of California San Diego; University of California System; University of California San Francisco; Banner Research; Banner Health; Banner Sun Health Research Institute; Banner Research; Banner Health; Banner Alzheimer's Institute; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Stanford University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4066
• DOI: 10.1038/s41586-024-07185-7
• 发表日期: 2024-04-04
• 关键词: a-beta; clearance; cells; cholesterol; macrophage; autophagy; tau

摘要

Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar A beta induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease. A microglial state, featuring lipid droplets and secretion of neurotoxic factors, is shown to be most prominent in people with Alzheimer's disease who have the APOE4 genotype.