Dissociation of Akt/PKB and ribosomal S6 kinase signaling markers in a transgenic mouse model of Alzheimer's disease
Dissociation of Akt/PKB and ribosomal S6 kinase signaling markers in a transgenic mouse model of Alzheimer's disease
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DOI：
10.1016/j.nbd.2007.09.008
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发表时间：
2008-02-01
影响因子：
6.1
通讯作者：
Page, Guylene
中科院分区：
文献类型：
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作者：
Damjanac, Milena;Bilan, Agnes Rioux;Page, Guylene
以往的研究表明，PKR（双链RNA活化蛋白激酶）途径被激活，而mTOR（雷帕霉素的哺乳动物靶蛋白）途径被抑制，在阿尔茨海默病（AD）。在这里，我们分析了APP（SL）/PS1 KI小鼠大脑中mTOR的上游和下游因素，这些小鼠在海马中显示出大量的神经元损失。虽然mTOR水平没有改变，但我们发现6个月龄时在非凋亡神经元中Akt的大量活化和P-Akt（（T308））的稳健积累。相反，在PS1 KI和APP（SL）/PS1 KI小鼠的脑中观察到p70/85 S6 K活化的显著降低，在APP（SL）/PS1 KI小鼠的凋亡神经元中具有非常弱或没有核胞质P-p70/85 S6 K（（T389））染色。此外，Erk 1/2、4 E-BP 1和p70 S6 K（（T421/S424））（Erk 1/2的底物）的活化，除eIF 4 E外，没有改变。这些发现表明这些小鼠中Akt和核糖体S6 K信号标记物之间存在明显的分离，这可能参与AD病理过程。(C)2007爱思唯尔公司All rights reserved.
Previous studies demonstrated that the PKR (double-stranded RNA -activated protein kinase) pathway was activated while the mTOR (mammalian target of rapamycin) pathway was inhibited in Alzheimer's disease (AD). Here, we analysed upstream and downstream factors of mTOR in brain of APP(SL)/PS1 KI mice displaying a massive neuronal loss in hippocampus. While mTOR levels were not modified, we found a great activation of Akt with a robust accumulation of P-Akt((T308)) in non-apoptotic neurons at 6 months of age. At the opposite, a significant decrease of the p70/85S6K activation was observed in brain of PS1 KI and APP(SL)/PS1 KI mice with a very weak or no nucleocytoplasmic P-p70/85S6K((T389)) staining in apoptotic neurons of APP(SL)/PS1 KI mice. Furthermore, the activation of Erk1/2, 4E-BP1 and p70S6K((T421/S424)) (substrate of Erk1/2), except eIF4E, was not modified. These findings demonstrate a clear dissociation between Akt and ribosomal S6K signaling markers in these mice which could be involved in the AD pathological process. (C) 2007 Elsevier Inc. All rights reserved.