Abstract GRK5 is a member of the G protein-coupled receptors (GPCRs) kinase family and is closely associated with Alzheimer's disease (AD). However, the biological function of GRK5 in the brain and the causal link between GRK5 deficiency and AD-like pathology is unknown. Here, we show that GRK5 is reduced in the AD mouse brain, and mice with reduced GRK5 in the hippocampus induce cognitive impairment. AD-like molecular pathology, such as significant neuronal damage and loss, enhanced tau proteins phosphorylation, and increased level of Aβ peptides in the hippocampus were also observed in the GRK5 deficiency mice. Mechanismly, GRK5 is located in microglia and plays an essential role in maintaining the morphology and function of microglia. CRK5 deficiency elicits microglial morphology change and pfo-inflammation-associated gene increase. In addition, transcriptional analysis of hippocampal tissues revealed that neuroactive ligand-receptor interactions and TNF signaling are striking changes in GRK5 deficiency mice, which have the same trend in the AD mouse. In conclusion, our results further confirm the vital role of GRK5 in maintaining normal cognitive function in mice. Provide a possible mechanism that GRK5 maintains the microglia homeostasis, and its loss may induce microglia function deficit and cause other AD-related molecular pathogenesis.