GPR34 regulation of disease-associated microglial states and responses to physiological stimuli

GPR34 is a microglia-enriched GPCR whose expression is downregulated under several disease conditions, including Alzheimer’s disease (AD) and multiple sclerosis (MS). Despite this, its function is poorly understood in normal or disease conditions, as is its contribution to disease-related microglia states. Using RNA-sequencing, we find that microglia from global Gpr34 knockout (KO) mouse brains exhibited transcriptional shifts toward disease-associated microglia (DAM) and inflammatory profiles, partially mirroring the microglial phenotype seen in 5xFAD AD model mice. Notably, when Gpr34 KO mice were crossed with 5xFAD mice, DAM transcriptional profiles and glial pathology were further exacerbated despite the already robust DAM signature driven by amyloidosis. This occurred without affecting amyloid plaque burden. In human stem cell-derived microglia (iMGLs), GPR34 KO strongly reduced calcium (Ca²⁺) and phosphorylated ERK (pERK) signaling in response to known GPR34 agonists, including lyso-phosphatidylserine (lysoPS) and myelin, and caused transcriptional alterations linked to immune regulation and cell proliferation. Interestingly, GPR34 loss selectively impaired phagocytosis of myelin but not amyloid-β or E. coli . Furthermore, GRP34 KO diminished, but did not abolish, the transcriptional response elicited by myelin. Together, these findings suggest that GPR34 is important for maintaining microglia homeostasis, mediating phagocytosis of and transcriptional response to myelin, and restraining microglial response to neurodegenerative disease conditions.