PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta.
PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta.
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DOI：
10.3233/jad-2010-1317
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发表时间：
2010
期刊：
影响因子：
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通讯作者：
Wei Qian;Jianhua Shi;Xiaomin Yin;K. Iqbal;I. Grundke‐Iqbal;C. Gong;Fei Liu
中科院分区：
文献类型：
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作者：
Wei Qian;Jianhua Shi;Xiaomin Yin;K. Iqbal;I. Grundke‐Iqbal;C. Gong;Fei Liu
tau 蛋白的异常过度磷酸化似乎在阿尔茨海默病 (AD) 的神经原纤维变性中至关重要。先前的研究表明，人脑中主要的 tau 磷酸酶蛋白磷酸酶 2A (PP2A) 的下调会导致 AD 中 tau 蛋白过度磷酸化。然而，PP2A 下调对位点特异性 tau 过度磷酸化的影响尚不清楚。在本研究中，我们发现 PP2A 在多个磷酸化位点以不同的效率使 tau 去磷酸化。在研究的位点中，Thr205、Thr212、Ser214和Ser262是体外PP2A最有利的位点，而Ser199和Ser404是PP2A最不利的位点。在代谢活跃的大鼠脑切片中用大田酸抑制 PP2A，通过增加其 Ser9 磷酸化而引起糖原合酶激酶 3beta (GSK-3beta) 的抑制。 GSK-3beta 在许多位点磷酸化 tau，其中 Ser199、Thr205 和 Ser396 是细胞中最有利的位点。 PP2A 抑制引起的 tau 磷酸化总体变化是直接抑制 PP2A 导致的 tau 去磷酸化减少和 GSK-3beta 抑制导致的磷酸化减少综合作用的结果。由于 tau 磷酸化对其生物活性和神经原纤维变性的影响具有位点特异性，因此本研究为 PP2A 下调在 AD 神经原纤维变性中的作用提供了新的见解。
Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in Alzheimer's disease (AD). Previous studies suggest that a down-regulation of protein phosphatase 2A (PP2A), the major tau phosphatase in human brain, contributes to tau hyperphosphorylation in AD. However, the effects of PP2A down-regulation on site-specific tau hyperphosphorylation is not well understood. In the present study, we showed that PP2A dephosphorylated tau at several phosphorylation sites with different efficiencies. Among the sites studied, Thr205, Thr212, Ser214, and Ser262 were the most favorable sites, and Ser199 and Ser404 were the least favorable sites for PP2A in vitro. Inhibition of PP2A with okadaic acid in metabolically active rat brain slices caused inhibition of glycogen synthase kinase-3beta (GSK-3beta) via an increase in its phosphorylation at Ser9. GSK-3beta phosphorylated tau at many sites, with Ser199, Thr205, and Ser396 being the most favorable sites in cells. The overall alterations in tau phosphorylation induced by PP2A inhibition were the result of the combined effects of both reduced tau dephosphorylation due to PP2A inhibition directly and reduced phosphorylation by GSK-3beta due to its inhibition. Because the impacts of tau phosphorylation on its biological activity and on neurofibrillary degeneration are site-specific, this study provides a new insight into the role of PP2A down-regulation in neurofibrillary degeneration in AD.