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

Michael S. Haney(Neurosciences Institute), Róbert Pálovics(Neurosciences Institute), Christy Munson(Neurosciences Institute), Chris M. Long(Stanford University), Patrik K. Johansson(Stanford University), Oscar Yip(Gladstone Institutes), Wentao Dong(Stanford University), Eshaan S. Rawat(Stanford University), Elizabeth West(University of California San Diego), Johannes C. M. Schlachetzki(University of California San Diego), Andy P. Tsai(Neurosciences Institute), Ian H. Guldner(Neurosciences Institute), Bhawika S. Lamichhane(Neurosciences Institute), Amanda Smith(Neurosciences Institute), Nicholas Schaum(Neurosciences Institute), Kruti Calcuttawala(Neurosciences Institute), Andrew Shin(Neurosciences Institute), Yung-Hua Wang(Gladstone Institutes), Chengzhong Wang(Gladstone Institutes), Nicole Koutsodendris(Gladstone Institutes), Geidy E. Serrano(Banner Sun Health Research Institute), Thomas G. Beach(Alzheimer's Association), Eric M. Reiman(Alzheimer's Association), Christopher K. Glass(University of California, San Francisco), Monther Abu-Remaileh(Stanford University), Annika Enejder(Stanford University), Yadong Huang(Gladstone Institutes), Tony Wyss‐Coray(Neurosciences Institute)
Nature
March 13, 2024
10.1038/s41586-024-07185-7
Cited by 453Open Access
Full Text

Abstract

. 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.

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