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

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 Aß (fAß) 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. Overall design: (1) Single-nucleus RNA-sequencing (snRNA-seq) on fresh-frozen frontal cortex tissue from individuals diagnosed with AD with the APOE4/4 genotype, individuals with AD and an APOE3/3 genotype and age and sex-matched control individuals with the APOE3/3 genotype. (2) RNA-seq of APOE4/4 iPSC-derived microglia (un)treated with fAß in the presence or absence of GNE-317. (3) FACS sorted lipid droplet high and low APOE4/4 and isogenic APOE3/3 iPSC-derived microglia (iMG) followed by ATAC-seq and RNA-seq.