Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation.
Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation.
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DOI：
10.1016/j.bbrc.2015.01.093
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发表时间：
2015-02-27
影响因子：
3.1
通讯作者：
Singh, Avtar K.
中科院分区：
文献类型：
--
作者：
Annamalai, Balasubramaniam;Won, Je-Seong;Choi, Seungho;Singh, Inderjit;Singh, Avtar K.
微管相关蛋白 tau 过度磷酸化并聚合成配对螺旋丝 (PHF) 是阿尔茨海默病 (AD) 的标志之一。在这里，我们报道 AD 条件下神经元 tau 过度磷酸化受到亚硝基谷胱甘肽 (GSNO)（一种内源性一氧化氮载体分子）的调节。在培养的大鼠皮质原代神经元中，我们观察到 GSNO 治疗降低了 β-淀粉样蛋白 (Aβ25-35) 诱导的病理性 tau 过度磷酸化（Ser396、Ser404 和 Ser202/Thr205）。 tau 过度磷酸化的减少与钙蛋白酶活性的降低以及 p35 蛋白水解为 p25 和 Cdk5 激活的减少相关。 GSNO 治疗还减弱了 Aβ25-35 诱导的 GSK-3β 激活，已知 GSK-3β 除 Cdk5 外，还在 tau 过度磷酸化中发挥关键作用。与上述使用培养神经元的研究一致，我们还观察到 AD 转基因小鼠模型 (APPSw/PS1dE9) 的全身 GSNO 治疗减弱了钙蛋白酶介导的 p35 蛋白水解和 Cdk5/GSK-3β 活性以及 tau 过度磷酸化。此外，GSNO 治疗为 APPSw/PS1dE9 小鼠提供神经和认知保护。这项研究首次描述了 GSNO 介导的 tau 蛋白过度磷酸化和认知功能调节，表明 GSNO 作为 AD 神经和认知保护剂的治疗潜力。
Hyperphosphorylation and polymerization of microtubule-associated protein tau into paired helical filaments (PHFs) is one of the hallmarks of Alzheimer’s disease (AD). Here we report that neuronal tau hyperphosphorylation under AD conditions is regulated by Snitrosoglutathione (GSNO), an endogenous nitric oxide carrier molecule. In cultured rat cortical primary neurons, we observed that GSNO treatment decreased the β-amyloid (Aβ25–35)-induced pathological tau hyperphosphorylation (Ser396, Ser404, and Ser202/Thr205). The decreased tau hyperphosphorylation correlated with decreased activity of calpain and decreased p35 proteolysis into p25 and Cdk5 activation. GSNO treatment also attenuated the Aβ25–35-induced activation of GSK-3β which is known to play critical role in tau hyperphosphorylation in addition to Cdk5. Consistent with above studies using cultured neurons, we also observed that systemic GSNO treatment of transgenic mouse model of AD (APPSw/PS1dE9) attenuated calpain-mediated p35 proteolysis and Cdk5/GSK-3β activities as well as tau hyperphosphorylation. In addition, GSNO treatment provided neuro- and cognitive protection in APPSw/PS1dE9 mice. This study describing the GSNO-mediated regulation of tau hyperphosphorylation and cognitive function, for the first time, suggests for therapeutic potential of GSNO as neuro- and cognitive-protective agent for AD.
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