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-3β (GSK-3β) 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-3β 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.
Highlights
Traumatic brain injury (TBI) can lead to death but can be a major cause of neurological and psychiatric disorders, such as headache,[1] post-traumatic stress disorder,[2] suicide[3] and cognitive dysfunction[4] in the chronic phase, even when the trauma is relatively mild.[5]
The area of lost tissue expanded gradually, and the hippocampus beneath the area of impact was badly damaged at 7 days after TBI and almost disappeared at 4 weeks after TBI (Figure 1a)
We demonstrate for we believe the first time that A2AR activation is closely related to TBI-induced impairments in spatial reference memory and working memory, and that the neurotoxic function of A2AR activation is probably mediated by the hyperphosphorylation of tau at Ser[404]
Summary
Traumatic brain injury (TBI) can lead to death but can be a major cause of neurological and psychiatric disorders, such as headache,[1] post-traumatic stress disorder,[2] suicide[3] and cognitive dysfunction[4] in the chronic phase, even when the trauma is relatively mild.[5] Blast exposure in combat, traffic accidents and high-contact sports such as boxing and American football are the main causes of TBI.[4,6] Nearly 20–30% of patients with Alzheimer’s disease (AD) or Parkinson's disease (PD) have a history of TBI, compared to only 8–10% of control subjects.[7] Learning and memory impairments may occur several years or decades after TBI. In many cases, this process is much faster and earlier than in other neurodegenerative diseases. AD-related lesions, such as hyperphosphorylated tau and amyloid-β accumulation, can be detected as early as 24 h after TBI in a mouse model.[8,9]
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