GPR50 regulates tau phosphorylation through the cAMP/PKA/GSK3β pathway

• 1、Institute of Neuroscience,Soochow University,Suzhou,Jiangsu Province 215123

Abstract：Objective: To explore the effect of orphan G protein-coupled receptor50 (GPR50) on tau phosphorylation and its underlying mechanism, and to find a new target for the treatment of Alzheimer's disease (AD). Methods: Firstly, mRNA and protein levels of GPR50 in brain tissue of APP/PS1 double transgenic AD model mice were analyzed by real-time fluorescence quantitative PCR and Western blot. Secondly, the regulation effect of GPR50 on tau and its phosphorylation levels was analyzed by using the GPR50 stably expressing cell lines or GPR50 knockout cell lines/animal, respectively. Furthermore, whether abnormally elevated phosphorylated tau level can be restored in AD model mice by using GPR50-AA8. Finally, Gαs, cAMP and PKA inhibitors were used to analyze the activity of GSK3β in cell lines of stably expressed GPR50,which is a key tau phosphorylated kinase, and the signal pathway of GPR50 regulating tau phosphorylation was analyzed. Results: The mRNA and protein levels of GPR50 were significantly decreased in AD mice. In animals or cells, GPR50 negatively regulates tau protein and its phosphorylation level in a post-transcription manner. Overexpression of GPR50 could rescue the abnormally elevated tau phosphorylation level in AD model mice. Even in GPR50 stably expressed cell lines, GSK3βkinase activity and tau phosphorylation levels increased significantly after Gαs, cAMP or PKA inhibitors application, which is consistent with that when GPR50 is knockdown. Conclusions: GPR50 regulates tau phosphorylation by activating the Gαs /cAMP/PKA/ GSK3β signaling cascade, which provides new strategies for the treatment of Alzheimer's disease and tau-related neurological diseases.

Keywords： Neurobiology Alzheimer's disease GPR50 tau cAMP GSK3β