BACKGROUND 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. RESULTS 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. CONCLUSIONS Akt may regulate tau phosphorylation in the adult brain by affecting activities for PKA and GSK3α.

中文翻译：

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Akt三种同工型的条件失活导致大脑中tau过度磷酸化。

背景技术Tau过度磷酸化在神经退行性疾病中起着至关重要的作用[EMBO Mol Med。6：1142-60，2014; 神经科学年鉴（Annu Rev Neurosci）。24：1121-59，2001]。最近的证据表明Akt在AD中被下调[J Pathol。225：54-62，2011]。但是，尚不清楚Akt可能促成哪种病理过程，例如tau病理或神经元死亡。在这项研究中，Cre-loxP技术被用于生成可行的Akt三种同工型条件敲除（Akt cTKO）小鼠，其中成年大脑中的总Akt水平显着降低。结果与年龄匹配的同窝幼仔对照组相比，Akt cTKO小鼠的各个部位的tau磷酸化（p-tau）水平显着增加。在Akt cTKO脑中检测到磷酸化的GSK3α和磷酸化的PKA底物水平升高。相比之下，在Akt1（-/-），Akt2（-/-）或Akt3（-/-）小鼠中未发现p-tau水平有明显变化。结论Akt可能通过影响PKA和GSK3α的活性来调节成人大脑中tau的磷酸化。