The G-protein coupled receptor GPR34 maintains the homeostatic state of microglia and restrains the disease-associated microglial response in an Alzheimers disease model

GPR34 loss in mouse microglia shifts transcriptomes toward disease-associated and inflammatory states, and worsens DAM and glial pathology in 5xFAD without changing amyloid plaque burden.

• Why it matters: GPR34 is enriched in microglia and downregulated in brain diseases, but its role in controlling microglial state and neuroinflammation is unclear.
• What they did: RNA-sequencing compared microglia from Gpr34 knockout mice and Gpr34/5xFAD crosses, and human stem cell-derived microglia lacking GPR34 were tested for Ca2+ and pERK signaling, myelin versus amyloid-B phagocytosis, and stimulation-driven transcriptional responses.
• The result: Gpr34 knockout microglia partially resemble DAM seen in 5xFAD, and combined loss further exacerbates DAM and pathology; in iMGLs, GPR34 deletion reduces lysoPS/myelin signaling, impairs myelin phagocytosis, and blunts myelin-evoked transcription.

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