Adenosine A2A receptor inactivation alleviates early-onset cognitive dysfunction after traumatic brain injury involving an inhibition of tau hyperphosphorylation.

ABSTRACT: 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 A2A receptors, either by caffeine or gene knockout (KO), alleviates cognitive dysfunction after traumatic brain injury (TBI). We postulated that A2AR 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 (A2AR antagonist ZM241385 or non-selective adenosine receptor antagonist caffeine) or genetic inactivation of A2ARs reduced the level of tau phosphorylation at Ser404 and alleviated spatial memory dysfunction. The A2AR control of p-tau is further supported by the observations that a KO of A2AR decreased the activity of the tau phosphorylation kinases, glycogen synthase kinase-3? (GSK-3?) and protein kinase A (PKA) after TBI, and by that CGS21680 (A2AR 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 (A2AR antagonist), H89 (PKA antagonist) and SB216763 (GSK-3? antagonist), or by the combined treatment with H89 and SB216763. Our findings suggest a novel mechanism whereby A2AR 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 A2AR signaling via tau phosphorylation.

SUBMITTER: Zhao ZA 

PROVIDER: S-EPMC5534966 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature