作者
Michael S. Haney,Róbert Pálovics,Christy Munson,Cheryl Long,Patrik Johansson,Oscar Yip,Wentao Dong,Eshaan S Rawat,Elizabeth West,J Schlachetzki,Andy P. Tsai,Ian H. Guldner,Bhawika S. Lamichhane,Amanda Smith,Nicholas Schaum,Kruti Calcuttawala,Andrew Shin,Sinan Wang,Chengzhong Wang,Nicole Koutsodendris,Geidy E. Serrano,Thomas G. Beach,Eric M. Reiman,Christopher K. Glass,Monther Abu-Remaileh,Annika Enejder,Yadong Huang,Tony Wyss‐Coray
摘要
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.