PP2A Regulates Tau Phosphorylation Directly and also Indirectly via Activating GSK-3β
PP2A Regulates Tau Phosphorylation Directly and also Indirectly via Activating GSK-3β
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DOI：
10.3233/jad-2009-1317
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
Liu, Fei
中科院分区：
文献类型：
--
作者：
Qian, Wei;Shi, Jianhua;Liu, Fei
tau蛋白的异常过度磷酸化似乎在阿尔茨海默病（AD）的神经退行性变中至关重要。以往的研究表明，蛋白磷酸酶2A（PP 2A），在人类大脑中的主要tau磷酸酶的下调，有助于在AD中的tau过度磷酸化。然而，PP 2A下调对位点特异性tau蛋白过度磷酸化的影响还不清楚。在本研究中，我们发现PP 2A在几个磷酸化位点以不同的效率去磷酸化tau蛋白。在所研究的位点中，Thr 205、Thr 212、Ser 214和Ser 262是PP 2A体外最有利的位点，Ser 199和Ser 404是PP 2A体外最不利的位点。在代谢活跃的大鼠脑切片中，用冈田酸抑制PP 2A可通过增加其Ser 9磷酸化而抑制糖原合成酶激酶-3 β（GSK-3 β）。GSK-3 β在许多位点磷酸化tau，其中Ser 199、Thr 205和Ser 396是细胞中最有利的位点。由PP 2A抑制诱导的tau磷酸化的总体改变是由于PP 2A直接抑制导致的tau去磷酸化减少和由于其抑制导致的GSK-3 β磷酸化减少两者的组合效应的结果。由于tau蛋白磷酸化对其生物学活性和神经退行性变的影响具有位点特异性，因此本研究为PP 2A下调在AD神经退行性变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-3 beta (GSK-3 beta) via an increase in its phosphorylation at Ser9. GSK-3 beta 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-3 beta 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.