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

Michael S. Haney, Róbert Pálovics, Christy Nicole Munson, Chris Long, Patrik K. Johansson, Oscar Yip, Wentao Dong, Eshaan Rawat, Elizabeth West, Johannes C. M. Schlachetzki, Andy Tsai, Ian Hunter Guldner, Bhawika S. Lamichhane, Amanda Smith, Nicholas Schaum, Kruti Calcuttawala, Andrew Shin, Yung-Hua Wang, Chengzhong Wang, Nicole Koutsodendris, Geidy E. Serrano, Thomas G. Beach, Eric M. Reiman, Christopher K. Glass, Monther Abu-Remaileh, Annika Enejder, Yadong Huang and Tony Wyss-Coray ()
Additional contact information
Michael S. Haney: Stanford University School of Medicine
Róbert Pálovics: Stanford University School of Medicine
Christy Nicole Munson: Stanford University School of Medicine
Chris Long: Stanford University School of Medicine
Patrik K. Johansson: Stanford University School of Medicine
Oscar Yip: Gladstone Institutes
Wentao Dong: Stanford University
Eshaan Rawat: Stanford University
Elizabeth West: University of California, San Diego
Johannes C. M. Schlachetzki: University of California, San Diego
Andy Tsai: Stanford University School of Medicine
Ian Hunter Guldner: Stanford University School of Medicine
Bhawika S. Lamichhane: Stanford University School of Medicine
Amanda Smith: Stanford University School of Medicine
Nicholas Schaum: Stanford University School of Medicine
Kruti Calcuttawala: Stanford University School of Medicine
Andrew Shin: Stanford University School of Medicine
Yung-Hua Wang: Gladstone Institutes
Chengzhong Wang: Gladstone Institutes
Nicole Koutsodendris: Gladstone Institutes
Geidy E. Serrano: Banner Sun Health Research Institute
Thomas G. Beach: Banner Alzheimer’s Institute and Arizona Alzheimer’s Consortium
Eric M. Reiman: Banner Alzheimer’s Institute and Arizona Alzheimer’s Consortium
Christopher K. Glass: University of California
Monther Abu-Remaileh: Stanford University
Annika Enejder: Stanford University School of Medicine
Yadong Huang: Gladstone Institutes
Tony Wyss-Coray: Stanford University School of Medicine

Nature, 2024, vol. 628, issue 8006, 154-161

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07185-7

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