• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>IBRO Reports >The impact of tau hyperphosphorylation at Ser262 on memory and learning after global brain ischaemia in a rat model of reversible cardiac arrest
【24h】

The impact of tau hyperphosphorylation at Ser262 on memory and learning after global brain ischaemia in a rat model of reversible cardiac arrest

机译：Ser 262 上的tau过度磷酸化对可逆性心脏骤停大鼠全脑缺血后记忆和学习的影响

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

An increase in phosphorylated tau (p-tau) is associated with Alzheimer's disease (AD), and brain hypoxia. Investigation of the association of residue-specific tau hyperphosphorylation and changes in cognition, leads to greater understanding of its potential role in the pathology of memory impairment. The aims of this study are to investigate the involvement of the main metabolic kinases, Liver Kinase B1 (LKB1) and Adenosine Monophosphate Kinase Protein Kinase (AMPK), in tau phosphorylation-derived memory impairment, and to study the potential contribution of the other tau kinases and phosphatases including Glycogen Synthase Kinase (GSK-3β), Protein kinase A (PKA) and Protein Phosphatase 2A (PP2A). Spatial memory and learning were tested in a rat global brain ischemic model of reversible cardiac arrest (CA). The phosphorylation levels of LKB1, AMPK, GSK-3β, PP2A, PKA and tau-specific phosphorylation were assessed in rats, subjected to ischaemia/reperfusion and in clinically diagnosed AD and normal human brains. LKB1 and AMPK phosphorylation increased 4 weeks after CA as did AMPK related p-tau (Ser 262 ). The animals showed unchanged levels of GSK-3β specific p-tau (Ser 202 /Thr 205 ), phospho-PP2A (Tyr 307 ), total GSK-3β, PP2A, phospho-cAMP response element-binding protein (CREB) which is an indicator of PKA activity, and no memory deficits. AD brains had hyperphosphorylated tau in all the residues of Ser 262 , Ser 202 and Thr 205 , with increased phosphorylation of both AMPK (Thr 172 ) and GSK-3β (Ser 9 ), and reduced PP2A levels. Our data suggests a crucial role for a combined activation of tau kinases and phosphatases in adversely affecting memory and that hyperphosphorylation of tau in more than one specific site may be required to create memory deficits. Highlights ? Short-term brain ischaemia causes AMPK activation and tau phosphorylation at its AMPK-sensitive site (Ser 262 ). ? Activation of GSK-3β, PP2A and PKA are remained unchanged in short-term brain ischaemia/reperfusion. ? In clinical cases of AD, activation of AMPK, GSK-3β, PP2A and multiple site hyperphosphorylation of tau are observed. ? Hyperphosphorylation of tau (Ser 262 ) alone without involving the other tau kinases/phosphatase does not affect memory.
机译：磷酸化tau（p-tau）的增加与阿尔茨海默氏病（AD）和脑缺氧有关。对残基特异性tau过度磷酸化与认知变化之间的关系的研究，导致人们对其记忆力受损病理学的潜在作用有了更深入的了解。这项研究的目的是调查主要代谢激酶，肝脏激酶B1（LKB1）和腺苷单磷酸激酶蛋白激酶（AMPK）在tau磷酸化引起的记忆障碍中的作用，并研究其他tau蛋白的潜在作用。激酶和磷酸酶，包括糖原合酶激酶（GSK-3β），蛋白激酶A（PKA）和蛋白磷酸酶2A（PP2A）。在可逆性心脏骤停（CA）的大鼠整体脑缺血模型中测试了空间记忆和学习。在大鼠，缺血/再灌注以及临床诊断的AD和正常人脑中，评估了LKB1，AMPK，GSK-3β，PP2A，PKA和tau特异性磷酸化水平。 CA后4周，LKB1和AMPK磷酸化增加，与AMPK相关的p-tau一样（Ser 262）。动物显示出不变水平的GSK-3β特异性p-tau（Ser 202 / Thr 205），磷酸-PP2A（Tyr 307），总GSK-3β，PP2A，磷酸-cAMP反应元件结合蛋白（CREB）。指示PKA活性，无记忆障碍。 AD脑在Ser 262，Ser 202和Thr 205的所有残基中具有高磷酸化的tau，同时AMPK（Thr 172）和GSK-3β（Ser 9）的磷酸化增加，PP2A水平降低。我们的数据表明，tau激酶和磷酸酶的联合激活在不利地影响记忆中​​起着至关重要的作用，并且可能需要tau在一个以上特定位点的过度磷酸化来造成记忆缺陷。强调 ？短期脑缺血可导致AMPK敏感部位的AMPK活化和tau磷酸化（Ser 262）。 ？在短期脑缺血/再灌注中，GSK-3β，PP2A和PKA的激活保持不变。 ？在AD的临床病例中，观察到AMPK，GSK-3β，PP2A的激活和tau的多位磷酸化。 ？单独使用tau（Ser 262）的过度磷酸化而不涉及其他tau激酶/磷酸酶不会影响记忆。

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