Dysregulation of tau phosphorylation in mouse brain during excitotoxic damage.
Dysregulation of tau phosphorylation in mouse brain during excitotoxic damage.
复制标题
DOI：
10.3233/jad-2009-1069
复制
发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Gong CX
中科院分区：
文献类型：
--
作者：
Liang Z;Liu F;Iqbal K;Grundke-Iqbal I;Gong CX
谷氨酸受体介导的兴奋性毒性被认为有助于阿尔茨海默病（AD）的发展，但其潜在机制尚不清楚。在本研究中，我们研究了在小鼠腹腔注射20 mg/kg红藻氨酸（KA）兴奋性毒性过程中，脑内tau蛋白磷酸化和tau蛋白相关蛋白激酶和蛋白磷酸酶2A（PP 2A）的动态变化。我们发现KA诱导的兴奋性毒性导致tau的瞬时去磷酸化（注射后6小时内），随后在AD脑中过度磷酸化的多个位点持续过度磷酸化tau。tau蛋白的初始去磷酸化可能是由于PP 2A的激活，而持续的过度磷酸化可能主要是由于cdk 5的激活和PP 2A在后期的下调。由于tau蛋白的异常过度磷酸化在神经退行性变和神经元缠结的形成中起着至关重要的作用，我们的研究结果表明，谷氨酸受体介导的兴奋性毒性可能部分通过促进AD脑中tau蛋白的异常过度磷酸化而导致AD。
Glutamate receptor-mediated excitotoxicity is thought to contribute to the development of Alzheimer’s disease (AD), but the underlying mechanism is unknown. In this study, we investigated the dynamic changes of tau phosphorylation and tau-related protein kinases and protein phosphatase 2A (PP2A) in the mouse brain during excitotoxicity induced by intraperitoneal injection of 20 mg/kg kainic acid (KA). We found that KA-induced excitotoxicity led to transient dephosphorylation of tau (within 6 hr post-injection), followed by sustained hyperphosphorylation of tau at multiple sites that are hyperphosphorylated in AD brain. The initial dephosphorylation of tau may result from activation of PP2A, and the sustained hyperphosphorylation may be due mainly to activation of cdk5 and down-regulation of PP2A during the later phase. Because abnormal hyperphosphorylation of tau plays a crucial role in neurodegeneration and in the formation of neurofibrillary tangles, our results suggest that glutamate receptor–mediated excitotoxicity might contribute to AD partially via promoting abnormal hyperphosphorylation of tau in AD brain.