Decrease of protein phosphatase 2A and its association with accumulation and hyperphosphorylation of tau in Down syndrome.
Decrease of protein phosphatase 2A and its association with accumulation and hyperphosphorylation of tau in Down syndrome.
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DOI：
10.3233/jad-2008-13307
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发表时间：
2008
期刊：
影响因子：
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通讯作者：
Zhihou Liang;Fei Liu;K. Iqbal;I. Grundke‐Iqbal;J. Wegiel;C. Gong
中科院分区：
文献类型：
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作者：
Zhihou Liang;Fei Liu;K. Iqbal;I. Grundke‐Iqbal;J. Wegiel;C. Gong
几乎所有患有唐氏综合征（DS）的个体在他们达到生命的第四个十年时都会发展神经元缠结，这是阿尔茨海默病（AD）的特征性脑损伤。在AD中，神经元缠结被认为是由tau蛋白的异常过度磷酸化引起的，而tau蛋白的异常过度磷酸化又可以由蛋白磷酸酶（PP）2A（一种主要的脑tau磷酸酶）的下调引起。在DS中tau蛋白的异常过度磷酸化尚未被表征，其原因也不清楚。在这项研究中，通过使用定量蛋白质印迹分析，我们发现PP 2A的催化亚基水平显着下降，但PP 1、PP 2B或PP 5的催化亚基水平没有显着下降。PP2A水平的降低与tau水平和tau蛋白在几个异常过度磷酸化位点（包括Ser199、Thr205、Thr212、Ser262、Ser396和Ser422）的磷酸化呈负相关。我们的研究结果表明，PP2A在DS脑下调，并建议这种下调可能参与异常过度磷酸化和tau蛋白的积累。
Virtually all individuals with Down syndrome (DS) develop neurofibrillary tangles, a characteristic brain lesion of Alzheimer's disease (AD), when they reach the fourth decade of life. In AD, neurofibrillary tangles are thought to result from abnormal hyperphosphorylation of tau protein, which, in turn, can result from down-regulation of protein phosphatase (PP) 2A, a major brain tau phosphatase. The abnormal hyperphosphorylation of tau in DS had not yet been characterized, and its causes were not understood. In this study, by using quantitative Western blot analysis, we found that the level of the catalytic subunit of PP2A, but not of PP1, PP2B or PP5, was dramatically decreased. The decrease of PP2A level correlated negatively to tau level and tau phosphorylation at several abnormal hyperphosphorylation sites, including Ser199, Thr205, Thr212, Ser262, Ser396 and Ser422. Our results indicate that PP2A is down-regulated in DS brain and suggest that this down-regulation might be involved in the abnormal hyperphosphorylation and accumulation of tau.