APOE4/4 is linked to damaging lipid droplets in Alzheimer’s 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)
bioRxiv (Cold Spring Harbor Laboratory)
July 25, 2023
10.1101/2023.07.21.549930
Cited by 20Open Access
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Abstract

Abstract Several genetic risk factors for Alzheimer’s Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar Aβ (fAβ) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD.

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