The cAMP-PKA pathway is the canonical pathway activated after A2AR activation, but its role in neurodegenerative diseases is still under debate.51 In recent years, some studies have demonstrated that over activation of PKA may induce cognitive dysfunction, and A2AR activation will ameliorate this effect.52, 53, 54 However, there is no evidence that PKA can directly phosphorylate Ser404 of tau protein, which is a target of GSK-3β.55 Interestingly, in our study, inactivation of either A2AR or PKA could decrease the level of phosphorylation at Ser404. Here, MAPT is linked to neurodegenerative disease.