GPR34 regulation of disease-associated microglial states in iMGL

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.