Forskolin Induces Hyperphosphorylation of Tau Accompanied by Cell Cycle Reactivation in Primary Hippocampal Neurons
Forskolin Induces Hyperphosphorylation of Tau Accompanied by Cell Cycle Reactivation in Primary Hippocampal Neurons
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Forskolin 诱导原代海马神经元中 Tau 蛋白过度磷酸化并伴随细胞周期重新激活
DOI：
10.1007/s12035-016-0348-7
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发表时间：
2016-12
影响因子：
5.1
通讯作者：
Zhang Lin
中科院分区：
文献类型：
--
作者：
Wang Hai-Hong;Li Yan;Li Ang;Yan Fang;Li Zhen-Lin;Liu Zhong-Ying;Zhang Lei;Zhang Jian;Dong Wei-Ren;Zhang Lin
异常过度磷酸化的tau蛋白是阿尔茨海默病（AD）患者大脑中神经原纤维缠结（nft）的主要蛋白质成分。细胞周期再激活被认为是阿尔茨海默病的重要神经病理特征，细胞周期调节因子的再表达和激活已知发生在含有nft的神经元中。本研究的目的是研究海马原代神经元tau过度磷酸化过程中的细胞周期再激活。我们使用PKA特异性激活剂forskolin在培养的原代海马神经元中诱导tau过度磷酸化，然后测量cyclin D1和cyclin B1的水平。我们发现forskolin诱导了tau蛋白在Ser214、Ser396和Ser202/Thr205位点的过度磷酸化，分别在6、12和12小时达到峰值，并在24小时恢复到正常水平。forskolin还诱导了持续的cAMP升高和PKA激活，在6小时达到峰值，这与蛋白磷酸酶2a （PP-2A）在24小时的激活和过度表达有关。tau过度磷酸化伴随着细胞周期蛋白D1和细胞周期蛋白B1水平的增加；免疫染色显示过度磷酸化的tau蛋白与细胞周期蛋白D1和细胞周期蛋白B1在原代海马神经元中重叠分布。在HEK293/tau441细胞中，Forskolin诱导tau过度磷酸化，增加了cyclin D1和cyclin B1蛋白水平，而在HEK293/载体细胞中则没有，而PKA抑制剂H89抑制了Forskolin对tau过度磷酸化和cyclin D1和cyclin B1蛋白水平的影响。这些发现表明，forskolin诱导tau过度磷酸化，这本身是随后cyclin D1和cyclin B1水平升高所必需的。
Abnormally hyperphosphorylated tau is the major protein constituent of neurofibrillary tangles (NFTs) in the brain of Alzheimer disease (AD) patients. Cell cycle reactivation is considered an important neuropathological feature of AD, and re-expression and activation of cell cycle regulators are known to occur in neurons containing NFTs. The aim of the present study was to investigate cell cycle reactivation during tau hyperphosphorylation in primary hippocampal neurons. We used forskolin, a specific activator of PKA, to induce tau hyperphosphorylation in cultured primary hippocampal neurons, and then measured levels of cyclin D1 and cyclin B1. We found that forskolin induced hyperphosphorylation of tau at Ser214, Ser396, and Ser202/Thr205 sites, attaining peak levels at 6, 12, and 12 h, respectively, while returning to normal levels at 24 h. Forskolin also induced a sustained cAMP elevation and PKA activation, which peaked at 6 h, in association with activation and overexpression of protein phosphatase-2A (PP-2A) at 24 h. The tau hyperphosphorylation was accompanied by increases in cyclin D1 and cyclin B1 levels; immunostaining showed overlapping distribution of hyperphosphorylated tau and cyclin D1 and cyclin B1 in primary hippocampal neurons. Forskolin induced hyperphosphorylation of tau and increased cyclin D1 and cyclin B1 protein levels in HEK293/tau441 cells, but not in the HEK293/vector cells, whereas the PKA inhibitor H89 inhibited the effects of forskolin on tau hyperphosphorylation and cyclin D1 and cyclin B1 protein levels. These findings suggest that forskolin induces tau hyperphosphorylation, which is itself necessary for the subsequent increases of cyclin D1 and cyclin B1 levels.
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影响因子：
168.9
作者：
T. C. Tsolakas;J. Davies;S. Oram
通讯作者：
T. C. Tsolakas;J. Davies;S. Oram
DOI：
10.1016/s0140-6736(86)92134-3
发表时间：
1986-08
期刊：
The Lancet
影响因子：
--
作者：
K. Iqbal;T. Zaidi;GuangY. Wen;I. Grundke‐Iqbal;P. Merz;Sadia Shaikh;H. Wisniewski;I. Alafuzoff-I.-Alafu
通讯作者：
K. Iqbal;T. Zaidi;GuangY. Wen;I. Grundke‐Iqbal;P. Merz;Sadia Shaikh;H. Wisniewski;I. Alafuzoff-I.-Alafu
DOI：
10.1038/jid.2010.62
发表时间：
2010-08
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Chi-hyun Park;Y. Moon;Chung Min Shin;J. Chung
通讯作者：
Chi-hyun Park;Y. Moon;Chung Min Shin;J. Chung
影响因子：
3.5
作者：
KHATOON, S;GRUNDKEIQBAL, I;IQBAL, K
通讯作者：
IQBAL, K
DOI：
10.1080/15384101.2015.1004937
发表时间：
2015
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Frade JM;Ovejero-Benito MC
通讯作者：
Ovejero-Benito MC