Valproate reduces tau phosphorylation via cyclin-dependent kinase 5 and glycogen synthase kinase 3 signaling pathways
Valproate reduces tau phosphorylation via cyclin-dependent kinase 5 and glycogen synthase kinase 3 signaling pathways
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丙戊酸通过细胞周期蛋白依赖性激酶 5 和糖原合酶激酶 3 信号通路减少 tau 磷酸化
DOI：
10.1016/j.brainresbull.2011.03.006
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发表时间：
2011-05-30
影响因子：
3.8
通讯作者：
Wang, Zhan-You
中科院分区：
文献类型：
--
作者：
Hu, Jiang-Ping;Xie, Jing-Wei;Wang, Zhan-You
丙戊酸（VPA）是一种广泛使用的抗惊厥和情绪稳定药物。最近的研究表明，VPA 可以减少 β 淀粉样蛋白的生成，并改善阿尔茨海默病 (AD) 转基因小鼠模型的记忆缺陷。然而，VPA是否影响tau磷酸化及其潜在机制尚未确定。在这里，我们发现用VPA（50 mg/kg，每天一次，持续12周）全身治疗APP和早老素1双转基因小鼠，显着降低了Thr205、Ser396和Thr231位点的tau磷酸化水平。同时，VPA 治疗显着降低了细胞周期蛋白依赖性激酶 5 (CDK5) 和糖原合酶激酶 3 beta (GSK3 beta) 的活性，这两种蛋白激酶参与 tau 异常过度磷酸化。在冈田酸诱导的 tau 蛋白过度磷酸化 SH-SY5Y 细胞模型中，进一步证实了 VPA 的抗 tau 蛋白磷酸化作用，同时伴随着 CDK5 和 GSK3 beta 活性的显着降低。我们目前的数据表明，VPA 对 tau 过度磷酸化的抑制作用可能是通过 CDK5 和 GSK3 β 信号通路介导的。 (C) 2011 Elsevier Inc. 保留所有权利。
Valproate (VPA) is a widely used anticonvulsant and mood-stabilizing drug. Recent studies have shown that VPA could reduce amyloid-beta generation, and improve memory deficits in transgenic mouse models of Alzheimer's disease (AD). However, whether VPA affects tau phosphorylation and the underlying mechanism has not been established. Here, we showed that systemic treatment of APP and presenilin 1 double transgenic mice with VPA (50 mg/kg, once a day for 12 weeks), significantly reduced the levels of tau phosphorylation at the sites of Thr205, Ser396 and Thr231. Meanwhile, VPA treatment markedly reduced the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 beta (GSK3 beta), two protein kinases involved in abnormal hyperphosphorylation of tau. In an okadaic acid-induced tau hyperphosphorylation SH-SY5Y cell model, the anti-tau-phosphorylation effect of VPA was further confirmed, accompanied by a marked decrease in the activities of CDK5 and GSK3 beta. Our present data suggest that the inhibitory effects of VPA on tau hyperphosphorylation might be mediated through both CDK5 and GSK3 beta signaling pathways. (C) 2011 Elsevier Inc. All rights reserved.