GPR34 regulates microglia state and loss-of-function rescues TREM2 metabolic dysfunction

Microglia are implicated in modifying neurodegenerative disease risk in the central nervous system (CNS). GPR34 is a microglia-enriched G-protein coupled receptor that detects cytotoxic lipids upregulated in Alzheimer’s Disease (AD). Since dysregulated lipid metabolism occurs in disease, we hypothesized GPR34 could act with other lipid sensors, such as TREM2, to regulate microglial function. Here, we report that GPR34 knockout (KO) rescues dysregulated cholesterol metabolism in TREM2 KO iPSC-derived microglia (iMG) and alone promotes fatty acid catabolism without the proton leak observed in TREM2 KO. Loss of GPR34 downregulated ERK signaling, while its agonism promoted interaction with and activation of ERK. In healthy and amyloid mouse models, Gpr34 KO accelerated the conversion of homeostatic microglia to disease-associated microglia (DAM) states. Additionally, in Gpr34 KO amyloid mouse brain, the frequency of large plaques was increased compared to WT, indicating that Gpr34 KO microglia may promote amyloid aggregation. Overall, our data suggest GPR34 as a therapeutic target for modulating microglial function to slow AD progression.