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

作者：Michael Haney, Róbert Pálovics, Christy N Munson, Chris M. Long, Patrik K. Johansson, Oscar Yip, Wentao Dong, E. Rawat, Elizabeth West, J. Schlachetzki, A. Tsai, Ian H. Guldner, B. S. Lamichhane, Amanda Smith, N. Schaum, K. Calcuttawala, Andrew Shin, Yung-Hua Wang, Chengzhong Wang, Nicole Koutsodendris, G. Serrano, T. Beach, E. Reiman, Christopher K. Glass, Monther Abu-Remaileh, Annika Enejder, Yadong Huang, T. Wyss‐Coray · 发表于：Nature · 年份：2024 · DOI：10.1038/s41586-024-07185-7 · 被引用次数：448 · 研究领域：Medicine

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 Aβ 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.