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Adhesion G protein-coupled receptor ADGRG1 promotes protective microglial response in Alzheimer’s disease

ABSTRACT: Microglia play critical roles in maintaining brain development, homeostasis, and response to aging and diseases like Alzheimer's disease (AD). Genetic studies highlight microglia's role in AD susceptibility, but the mechanisms mediating protective responses remain largely unknown. Gpr56/Adgrg1, is one of the few genes specifically expressed in yolk-sac-derived microglia, as compared with other mononuclear phagocytes. This study reveals its role in AD pathology, particularly in modulating microglial protective responses to amyloid deposition. Utilizing constitutive and inducible microglial Adgrg1 knockouts in the 5xFAD mouse model, we demonstrate that Adgrg1 deficiency leads to increased amyloid deposition, exacerbated neuropathology, and accelerated cognitive impairment. Transcriptomic analyses reveal a distinct microglial state characterized by downregulated genes associated with homeostasis, phagocytosis, and lysosomal functions. Functional assays in mouse models and human iPSC-derived microglia support the requirement for microglial ADGRG1 in efficient Aβ phagocytosis. Collectively, these results uncover a GPCR-dependent mechanism that instructs beneficial microglial functions in response to Aβ, pointing towards potential therapeutic strategies designed to alleviate disease progression by enhancing microglial functional competence.

ORGANISM(S): Mus musculus

PROVIDER: GSE273690 | GEO | 2025/07/25

REPOSITORIES: GEO

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