TREM2 Regulates Microglial Cholesterol Metabolism Upon Chronic Phagocytic Challenge
85 Pages Posted: 3 Sep 2019 Sneak Peek Status: Review CompleteMore...
Loss of function (LOF) variants of TREM2, an immune receptor expressed in microglia, increase Alzheimer’s disease (AD) risk. TREM2 senses lipids and mediates myelin phagocytosis, but its role in microglial lipid metabolism is unknown. Combining chronic demyelination paradigms and cell sorting techniques with RNA sequencing and lipidomics, we found that wildtype microglia acquire a disease-associated microglia transcriptional state, while TREM2-deficient microglia remain largely homeostatic, leading to neuronal damage. TREM2-deficient microglia maintain phagocytic activity of myelin debris, but are incompetent at clearing myelin lipids, including cholesterol, resulting in cholesteryl ester (CE) accumulation. CE increase was also observed in APOE-deficient glial cells, reflecting impaired brain cholesterol transport. This finding was replicated in myelin-treated TREM2-deficient murine macrophages and human iPSC-derived microglia, where it was rescued by an ACAT1 inhibitor and LXR agonist. Our studies identify TREM2 as a key transcriptional regulator of cholesterol transport and metabolism under conditions of chronic myelin phagocytic activity, as TREM2 LOF causes pathogenic lipid accumulation in microglia.
Keywords: microglia, Lipid metabolism, lipid dysregulation, cholesterol, cholesteryl ester, TREM2, ApoE, myelin, neurodegeneration, Alzheimer's disease, phagocytosis
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