GRK5 Deficiency in the Hippocampus Leads to Cognitive Impairment via Abnormal Microglial Alterations

GRK5 is a member of the G protein-coupled receptor (GPCR) kinase family and is closely associated with heart and nervous system disease. It has been reported that GRK5 is closely related to cerebral nerve function and neurodegenerative diseases. However, the biological function of GRK5 in the brain and the influence of GRK5 deficiency on cognitive dysfunction associated with neurodegenerative diseases are unknown. Here, we reported that mice with reduced GRK5 in the hippocampus exhibit cognitive impairment and some Alzheimer's disease (AD)-related molecular pathologies, such as significant neuronal damage and loss, enhanced tau protein phosphorylation, and increased levels of Aβ peptides in the hippocampus. Mechanistically, we observed that GRK5 is located in microglia and plays an essential role in maintaining the morphology and function of microglia. GRK5 deficiency elicits microglial morphology changes and proinflammatory-associated gene increases. In addition, transcriptional analysis of hippocampal tissues revealed striking changes in neuroactive ligand‒receptor interactions and TNF signaling in GRK5-deficient mice. In conclusion, our results further confirm the vital role of GRK5 in maintaining normal cognitive function in mice. This finding suggests a possible mechanism by which GRK5 maintains microglial homeostasis, and its loss may induce microglial function deficits and cause some AD-related molecular pathogenesis.