Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain
Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain
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DOI：
10.1111/j.1742-4658.2005.04833.x
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发表时间：
2005-08-01
期刊：
影响因子：
5.4
通讯作者：
Pei, JJ
中科院分区：
文献类型：
--
作者：
Li, X;Alafuzoff, I;Pei, JJ
阿尔茨海默病（AD）脑中神经元缠结（NFT）形成的发病机制尚不清楚。其中一种可能性可能是tau mRNA的翻译在AD脑中受到异常调节。在本研究中，各种翻译控制元件，包括总的和磷酸化（p）形式的哺乳动物雷帕霉素靶蛋白（mTOR），真核起始因子4 E结合蛋白1（4 E-BP 1），真核延伸因子2（eEF 2），和eEF 2激酶的水平与tau蛋白的内侧颞叶皮层匀浆从20 AD和10个对照组的大脑进行了研究。我们发现，p-mTOR（Ser 2481）和p-4 E-BP 1（Thr 70和Ser 65）的水平在AD中显著增加，并且与总tau和p-tau显著正相关。与对照组相比，AD患者p-eEF 2K水平显著升高，总eEF 2水平显著降低。免疫组化证实AD脑神经元中存在p-mTOR（2481）、p-4 E-BP 1和p-eEF 2的变化。提示AD脑内与翻译调控相关的元件存在明显异常，其异常变化可能上调tau mRNA的翻译，导致NFT神经元内tau蛋白过度磷酸化。
The pathogenesis of formation of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains is unknown. One of the possibilities might be that translation of tau mRNA is aberrantly regulated in AD brains. In the current study, levels of various translation control elements including total and phosphorylated (p) forms of mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E binding protein 1 (4E-BP1), eukaryotic elongation factor 2 (eEF2), and eEF2 kinase were investigated in relationship with tau in homogenates of the medial temporal cortex from 20 AD and 10 control brains. We found that levels of p-mTOR (Ser2481), and p-4E-BP1 (Thr70 and Ser65) dramatically increase in AD, and are positively significantly correlated with total tau and p-tau. Levels of p-eEF2K were significantly increased, and total eEF2 significantly decreased in AD, when compared to controls. The changes of p-mTOR (2481), p-4E-BP1, and p-eEF2 were immunohistochemically confirmed to be in neurons of AD brains. This suggested that there are obvious abnormalities of elements related with translation control in AD brain and their aberrant changes may up-regulate the translation of tau mRNA, contributing to hyperphosphorylated tau accumulation in NFT-bearing neurons.