Bulk transcriptome analysis of wildtype, TREM2 knockout, GPR34 knock-out or TREM2/GPR34 double knock-out iPSC-derived human microglia treated either with PBS or myelin.

Microglia are broadly implicated in modifying disease risk in the central nervous system (CNS). Identifying regulators of microglia state is critical for elucidating their role in disease and identifying novel drug targets. GPR34 is a G-protein coupled receptor expressed in homeostatic microglia where its function is not well understood. Like TREM2, GPR34 detects lipid ligands. Here, we report that GPR34 knockout (KO) maintains lipid homeostasis and rescues dysregulated cholesterol metabolism in TREM2 KO human iPSC-derived microglia (iMG). Loss of GPR34 reduced ERK signaling in iMG, which has been implicated as a signaling pathway dysregulated in AD, with GPR34 agonism shown to promote GPR34 interaction with ERK in a matter consistent with endosomal signaling. In both healthy and amyloid mouse models, Gpr34 KO accelerated microglial state transcriptionally and histologically consistent conversion of homeostatic microglia to a disease-associated microglia (DAM) state. Shifts in microglial state were accompanied by increased expression of multiple metabolic gene sets.