Wang Long, Cheng Shanshan, Yin Zhenyu, Xu Congyu, Lu Shuangshuang, Hou Jinxing, Yu Tingting, Zhu Xiaolei, Zou Xiaoyan, Peng Ying, Xu Yun, Yang Zhongzhou, Chen Guiquan
Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, 12 Xuefu Avenue, Nanjing, Jiangsu Province, 210061, China.
Department of Geriatric, Nanjing Drum Tower Hospital, Nanjing University Medical School, 321 Zhongshan Avenue, Nanjing, Jiangsu Province, 210008, China.
Mol Neurodegener. 2015 Jul 31;10:33. doi: 10.1186/s13024-015-0030-y.
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.
tau蛋白过度磷酸化在神经退行性疾病中起关键作用[《欧洲分子生物学组织分子医学》。6:1142 - 60, 2014；《神经科学年度评论》。24:1121 - 59, 2001]。最近的证据表明，Akt在阿尔茨海默病中表达下调[《病理学杂志》。225:54 - 62, 2011]。然而，Akt可能参与哪种病理过程，例如tau蛋白病变或神经元死亡，仍不清楚。在本研究中，采用Cre-loxP技术生成了一种存活的Akt三种亚型条件性敲除（Akt cTKO）小鼠，其中成年大脑中的总Akt水平显著降低。
与年龄匹配的同窝对照相比，在Akt cTKO小鼠中观察到多个位点的tau蛋白磷酸化（p-tau）水平显著升高。在Akt cTKO大脑中检测到磷酸化GSK3α和磷酸化PKA底物水平升高。相比之下，在Akt1(-/-)、Akt2(-/-)或Akt3(-/-)小鼠中未发现p-tau水平有显著变化。
Akt可能通过影响PKA和GSK3α的活性来调节成年大脑中的tau蛋白磷酸化。
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