Adenosine A(2A) receptor inactivation alleviates early-onset cognitive dysfunction after traumatic brain injury involving an inhibition of tau hyperphosphorylation

Tau is a microtubule-associated protein, and the oligomeric and hyperphosphorylated forms of tau are increased significantly after neurotrauma and considered important factors in mediating cognitive dysfunction. Blockade of adenosine A(2A) receptors, either by caffeine or gene knockout (KO), alleviates cognitive dysfunction after traumatic brain injury (TBI). We postulated that A(2A)R activation exacerbates cognitive impairment via promoting tau hyperphosphorylation. Using a mouse model of moderate controlled cortical impact, we showed that TBI induced hyperphosphorylated tau (p-tau) in the hippocampal dentate gyrus and spatial memory deficiency in the Morris water maze test at 7 days and 4 weeks after TBI. Importantly, pharmacological blockade (A(2A)R antagonist ZM241385 or non-selective adenosine receptor antagonist caffeine) or genetic inactivation of A(2A)Rs reduced the level of tau phosphorylation at Ser404 and alleviated spatial memory dysfunction. The A(2A)R control of p-tau is further supported by the observations that a KO of A(2A)R decreased the activity of the tau phosphorylation kinases, glycogen synthase kinase-3β (GSK-3β) and protein kinase A (PKA) after TBI, and by that CGS21680 (A(2A)R agonist) exacerbated okadaic acid-induced tau hyperphosphorylation in cultured primary hippocampal neurons. Lastly, CGS21680-induced neuronal tau hyperphosphorylation and axonal injury were effectively alleviated by individual treatments with ZM241385 (A(2A)R antagonist), H89 (PKA antagonist) and SB216763 (GSK-3β antagonist), or by the combined treatment with H89 and SB216763. Our findings suggest a novel mechanism whereby A(2A)R activation triggers cognitive dysfunction by increasing the phosphorylation level of tau protein after TBI and suggest a promising therapeutic and prophylactic strategy by targeting aberrant A(2A)R signaling via tau phosphorylation.