TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism

Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and sequence variants are major risk factors for late onset Alzheimer’s disease (LOAD). Using a reporter model, we observed a gradual upregulation of TREM2 with increasing plaque proximity. Isolated microglia were sorted based on reporter expression, to determine fluorodeoxyglucose (FDG) uptake and the metabolomic, lipidomic, and transcriptomic signatures. Uptake of FDG correlated with the gradual increase of TREM2 expression. TREM2 expression improved cellular redox, energetics, and cholesterol homeostasis in the presence or absence of amyloid pathology. Bulk RNA sequencing analysis identified major changes in immunometabolic pathways. Genes associated with oxidative phosphorylation or cholesterol homeostasis were enriched in the TREM2 high expressing clusters. Finally, chronic treatment with a brain penetrant TREM2 agonist identified a window of TREM2 expression where microglia are most accessible for protective responses providing important information for the current efforts to bring TREM2 agonists into the clinic.