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

Germline genetic architecture of Alzheimer's disease (AD) indicates microglial mechanisms of disease susceptibility and outcomes. However, the mechanisms enabling protective microglial responses remain elusive. Here, we investigate the role of microglial ADGRG1, an adhesion G-protein-coupled receptor (aGPCR) specifically expressed in yolk-sac-derived microglia, in AD pathology using the 5xFAD mouse model. Transcriptomic analyses reveal that ADGRG1 activates the transcription factor MYC, leading to upregulation of genes involved in homeostasis, phagocytosis, and lysosomal functions, thereby promoting a protective microglial state. We demonstrate that deletion of Adgrg1 in microglia impairs MYC activation, resulting in increased amyloid-beta deposition, exacerbated neuronal loss, and cognitive deficits. Functional assays in mouse models and human embryonic stem cell-derived microglia confirm that ADGRG1 is required for Aß phagocytosis. These findings uncover a GPCR-mediated pathway that drives a protective microglial state via MYC activation, suggesting potential therapeutic strategies to alleviate AD progression by enhancing microglial functional competence. Overall design: To investigate the role of microglial Adgrg1 in AD pathology, we engineered a novel mouse model and performed snRNAseq on the neocortex of 6-month-old animal. To enrich glial cells, each animal was sorted by DAPI-positive and DAPI-positive NeuN-negative nuclei before sequencing. The genotypes for the testing animals are: Adgrg1+/+;Cx3cr1Cre/+ (Con); Adgrg1fl/fl;Cx3cr1Cre/+ (CKO); 5xFAD;Adgrg1+/+;Cx3cr1Cre/+ mice (ADCon); 5xFAD;Adgrg1fl/fl;Cx3cr1Cre/+ (ADCKO).