Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils

Abstract

Microglia, the primary immune cells of the central nervous system, play a crucial role in maintaining brain homeostasis through phagocytosis of various substrates, including amyloid-β (Aβ) fibrils, a hallmark of Alzheimer disease (AD) pathology. However, the molecular mechanisms regulating microglial Aβ uptake remain poorly understood. Here, we identified GPR34, a Gi/o-coupled receptor highly expressed in microglia, as a novel regulator of fibrillar Aβ phagocytosis. Treatment with a selective GPR34 agonist, M1, specifically enhanced uptake of Aβ fibrils, but not its monomer or oligomer, in both mouse and human microglia. Mechanistically, M1 reduced intracellular cAMP levels, which inversely correlated with Aβ uptake activity. Importantly, a single intrahippocampal injection of M1 in an AD mouse model significantly increased microglial Aβ uptake in vivo. Furthermore, single-nucleus RNA-sequencing analysis of Japanese AD patient samples revealed a significant reduction of GPR34 expression in microglia from AD patients compared to controls. We also observed an age-dependent decline in microglial GPR34 expression in both human and mouse datasets, suggesting a potential contribution of GPR34 downregulation to age-related Aβ accumulation and AD risk. Collectively, our findings identify GPR34 as a promising target for modulating microglial Aβ clearance and highlight the therapeutic potential of GPR34 agonists in AD.