Conditional inactivation of Akt three isoforms causes tau hyperphosphorylation in the brain.
Conditional inactivation of Akt three isoforms causes tau hyperphosphorylation in the brain.
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Akt 三种亚型的条件性失活会导致大脑中 tau 蛋白过度磷酸化。
DOI：
10.1186/s13024-015-0030-y
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发表时间：
2015-07-31
影响因子：
15.1
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Wang L;Cheng S;Yin Z;Xu C;Lu S;Hou J;Yu T;Zhu X;Zou X;Peng Y;Xu Y;Yang Z;Chen G
Tau过度磷酸化在神经退行性疾病中起关键作用[EMBO Mol Med. 6:1142- 60,2014；中华神经科学杂志，2004,24(2):391 - 391。近年来研究表明，Akt在阿尔茨海默病中的表达下调[J].中华病理学杂志，2011,25(5):554 - 562。然而，Akt可能参与的病理过程（如tau病理或神经元死亡）尚不清楚。在本研究中，采用Cre-loxP技术产生了Akt三异构体条件敲除（Akt cTKO）小鼠，其成年大脑中总Akt水平显著降低。Akt cTKO小鼠中各位点的tau磷酸化水平（p-tau）均显著高于同龄对照组。Akt cTKO脑组织中磷酸化GSK3α和磷酸化PKA底物水平升高。相比之下，在Akt1−/−、Akt2−/−或Akt3−/−小鼠中p-tau水平未发现显著变化。Akt可能通过影响PKA和GSK3α的活性来调节成人脑中的tau磷酸化。本文的在线版本（doi:10.1186/s13024-015-0030-y）包含补充资料，仅供授权用户使用。
Tau hyperphosphorylation plays a critical role in neurodegenerative diseases [EMBO Mol Med. 6:1142-60, 2014; Annu Rev Neurosci. 24:1121-59, 2001]. Recent evidence has shown that Akt is down-regulated in AD [J Pathol. 225:54-62, 2011]. However, it remained unknown which pathological process, e.g. tau pathology or neuron death, Akt may contribute to. In this study, Cre-loxP technique was employed to generate a viable Akt three isoforms conditional knockout (Akt cTKO) mouse in which total Akt levels were dramatically reduced in the adult brain. Significantly increased levels of tau phosphorylated (p-tau) at various sites were observed in Akt cTKO mice as compared to age-matched littermate controls. Increased levels for phosphorylated GSK3α and phosphorylated PKA substrates were detected in Akt cTKO brains. In contrast, no significant changes on p-tau levels were found in Akt1−/−, Akt2−/− or Akt3−/− mice. Akt may regulate tau phosphorylation in the adult brain by affecting activities for PKA and GSK3α. The online version of this article (doi:10.1186/s13024-015-0030-y) contains supplementary material, which is available to authorized users.