APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.
Michael S HaneyRóbert PálovicsChristy Nicole MunsonChris LongPatrik K JohanssonOscar YipWentao DongEshaan RawatElizabeth WestJohannes C M SchlachetzkiAndy Po-Yi TsaiIan Hunter GuldnerBhawika S LamichhaneAmanda SmithNicholas SchaumKruti CalcuttawalaAndrew ShinYung-Hua WangChengzhong WangNicole KoutsodendrisGeidy E SerranoThomas G BeachEric M ReimanChristopher K GlassMonther Abu-RemailehAnnika M K EnejderYadong HuangTony Wyss-CorayPublished in: Nature (2024)
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 cells 1 . 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.