...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Tau phosphorylation and neuronal apoptosis induced by the blockade of PP2A preferentially involve GSK3beta.
【24h】

Tau phosphorylation and neuronal apoptosis induced by the blockade of PP2A preferentially involve GSK3beta.

机译：阻止PP2A诱导的Tau磷酸化和神经元凋亡优先涉及GSK3beta。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Overactivation of GSK3beta (glycogen synthase kinase-3beta) and downregulation of PP2A (protein phosphatase-2A) have been proposed to be involved in the abnormal tau phosphorylation and aggregation in Alzheimer's disease (AD). GSK3beta and PP2A signaling pathways were reported to be interconnected. Targeting tau kinases was suggested to represent a therapeutic strategy for AD. Here, tau phosphorylation and neuronal apoptosis were induced in cortical cultured neurons by the inhibition of PP2A by okadaic acid (OKA). In this in vitro model of 'tau pathology' and neurodegeneration, we tested whether GSK3beta and other tau kinases including DYRK1A and CDK5 were implicated. Our results show that the inhibitors of GSK3beta, lithium and 6-BIO (6-bromoindirubin-3'-oxime), prevented OKA-induced tau phosphorylation and neuronal apoptosis. The implication of GSK3beta in these OKA-induced effects was confirmed by its silencing by hairpin siRNA. By contrast, inhibition of DYRK1A (dual-specificity tyrosine-phosphorylation regulated kinase-1A) and CDK5 (cyclin-dependent kinase-5) reversed OKA-induced tau phosphorylation at certain sites but failed to prevent neuronal apoptosis. These results indicate that OKA-induced effects, especially neuronal apoptosis, are preferentially mediated by GSK3beta. Furthermore, since chronic exposure to lithium and 6-BIO might be deleterious for neurons, we tested the effect of a new 6-BIO derivative, 6-BIBEO (6-bromoindirubin-3'-(2-bromoethyl)-oxime), which is much less cytotoxic and more selectively inhibits GSK3beta compared to lithium and 6-BIO. We show that 6-BIBEO efficiently reversed OKA-induced tau phosphorylation and neuronal apoptosis. It will be interesting to test neuroprotection by 6-BIBEO in an in vivo model of tau pathology and neurodegeneration.
机译：GSK3beta（糖原合酶激酶-3beta）的过度激活和PP2A（蛋白磷酸酶-2A）的下调被认为与阿尔茨海默病（AD）的异常tau磷酸化和聚集有关。 GSK3beta和PP2A信号通路据报道是相互联系的。建议靶向tau激酶代表AD的治疗策略。在这里，通过冈田酸（OKA）抑制PP2A，在皮层培养的神经元中诱导tau磷酸化和神经元凋亡。在这种“ tau病理学”和神经变性的体外模型中，我们测试了是否牵涉到GSK3beta和包括DYRK1A和CDK5在内的其他tau激酶。我们的研究结果表明，GSK3β，锂和6-BIO（6-溴代靛红3'-肟）的抑制剂可阻止OKA诱导的tau磷酸化和神经元凋亡。 GSK3beta在这些OKA诱导的效应中的作用已通过发夹siRNA的沉默得以证实。相比之下，对DYRK1A（双重特异性酪氨酸磷酸化调节激酶1A）和CDK5（细胞周期蛋白依赖性激酶5）的抑制会逆转OKA诱导的某些部位的tau磷酸化，但不能阻止神经元凋亡。这些结果表明，OKA诱导的效应（尤其是神经元凋亡）优先由GSK3beta介导。此外，由于长期暴露于锂和6-BIO对神经元可能有害，因此我们测试了新型6-BIO衍生物6-BIBEO（6-bromoindirubin-3'-（2-bromoethyl）-肟）的作用。与锂和6-BIO相比，它具有更低的细胞毒性，并更有选择性地抑制GSK3beta。我们显示6-BIBEO有效地逆转了OKA诱导的tau磷酸化和神经元凋亡。在tau病理和神经退行性变的体内模型中测试6-BIBEO对神经的保护将是有趣的。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号