Adenosine A(2A) receptor inactivation alleviates early-onset cognitive dysfunction after traumatic brain injury involving an inhibition of tau hyperphosphorylation.
Adenosine A(2A) receptor inactivation alleviates early-onset cognitive dysfunction after traumatic brain injury involving an inhibition of tau hyperphosphorylation.
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腺苷 A(2A) 受体失活可减轻创伤性脑损伤后的早发认知功能障碍，涉及抑制 tau 过度磷酸化
DOI：
10.1038/tp.2017.98
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发表时间：
2017-05-09
影响因子：
6.8
通讯作者：
Zhou YG
中科院分区：
文献类型：
--
作者：
Zhao ZA;Zhao Y;Ning YL;Yang N;Peng Y;Li P;Chen XY;Liu D;Wang H;Chen X;Bai W;Chen JF;Zhou YG
Tau是一种微管相关蛋白，其寡聚体和过度磷酸化形式在神经创伤后显著增加，被认为是调节认知功能障碍的重要因素。通过咖啡因或基因敲除(KO)阻断腺苷A2a受体，可减轻创伤性脑损伤(TBI)后的认知功能障碍。我们推测A2AR的激活通过促进tau的过度磷酸化而加重认知损害。采用中度可控性皮质撞击小鼠模型，在7d和4周时，在Morris水迷宫实验中发现，脑损伤后7d和4周，大鼠海马齿状回出现过度磷酸化的tau蛋白(p-tau)，空间记忆能力下降。重要的是，药物阻断(A2AR拮抗剂ZM241385或非选择性腺苷受体拮抗剂咖啡因)或A2ARs的遗传失活降低了Ser404的tau磷酸化水平，并缓解了空间记忆功能障碍。A2AR激动剂CGS21680加重了冈田酸诱导的原代培养海马神经元tau蛋白过度磷酸化，进一步支持了A2AR对p-tau的控制作用，观察到A2AR的KO降低了脑损伤后原代培养的海马神经元tau磷酸化激酶、糖原合成酶β和蛋白激酶A的活性，并且A2AR激动剂CGS21680加重了冈田酸诱导的原代培养海马神经元tau过度磷酸化。A2AR拮抗剂ZM241385、PKA拮抗剂H89和GSK-3β拮抗剂SB216763单独或联合应用可有效减轻CGS21680诱导的神经元tau过度磷酸化和轴突损伤。我们的发现提示了一种新的机制，即A2AR激活通过增加tau蛋白的磷酸化水平来触发认知功能障碍，并通过tau蛋白的磷酸化来靶向A2AR信号的异常，从而提出了一种有前景的治疗和预防策略。
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.
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影响因子：
17.1
作者：
Goldstein LE;Fisher AM;Tagge CA;Zhang XL;Velisek L;Sullivan JA;Upreti C;Kracht JM;Ericsson M;Wojnarowicz MW;Goletiani CJ;Maglakelidze GM;Casey N;Moncaster JA;Minaeva O;Moir RD;Nowinski CJ;Stern RA;Cantu RC;Geiling J;Blusztajn JK;Wolozin BL;Ikezu T;Stein TD;Budson AE;Kowall NW;Chargin D;Sharon A;Saman S;Hall GF;Moss WC;Cleveland RO;Tanzi RE;Stanton PK;McKee AC
通讯作者：
McKee AC
影响因子：
4.2
作者：
Canas, Paula M.;Duarte, Joao M. N.;Cunha, Rodrigo A.
通讯作者：
Cunha, Rodrigo A.
影响因子：
2.9
作者：
ADAMS, JA;MCGLONE, ML;TAYLOR, SS
通讯作者：
TAYLOR, SS
影响因子：
5.3
作者：
Dall'Igna, Oscar P.;Fett, Paulo;Lara, Diogo R.
通讯作者：
Lara, Diogo R.
影响因子：
25.8
作者：
Bryan, Craig J.;Clemans, Tracy A.
通讯作者：
Clemans, Tracy A.