Neuropathogenic role of adenylate kinase-1 in A-mediated tau phosphorylation via AMPK and GSK3
Neuropathogenic role of adenylate kinase-1 in A-mediated tau phosphorylation via AMPK and GSK3
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DOI：
10.1093/hmg/dds100
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发表时间：
2012-06-15
影响因子：
3.5
通讯作者：
Jung, Yong-Keun
中科院分区：
文献类型：
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作者：
Park, Hyejin;Kam, Tae-In;Jung, Yong-Keun
tau 蛋白异常过度磷酸化通常是由 tau 激酶（例如 GSK3 和 Cdk5）引起的。这种情况会导致神经原纤维缠结的形成和 tau 蛋白病（包括阿尔茨海默病 (AD)）中的神经元变性。然而，人们对 A(42) tau 病理性磷酸化背后的信号级联反应知之甚少。在这项研究中，我们证明腺苷酸激酶 1 (AK1) 是异常 tau 磷酸化的新型调节因子。 AK1 表达在 AD 患者和 AD 模型小鼠的大脑中显着增加，并且在初级神经元中受到 A(42) 的显着诱导。单独的 AK1 异位表达会增强 tau 在 PHF1、CP13 和 AT180 表位处的病理性磷酸化，并增强 tau 聚集体的形成。相反，AK1 的下调可减轻 A(42) 诱导的 tau 蛋白过度磷酸化。 AK1 在 A(42) 诱导的原代神经元 AMPK 活性和 GSK3 激活受损中发挥作用。药理学研究表明，AMPK 抑制剂治疗可激活 GSK3，而 GSK3 抑制剂可减弱 AK1 介导的 tau 磷酸化。在人类 tau 蛋白病的果蝇模型中，人 AK1 的视网膜表达严重加剧了粗糙的眼睛表型并增加了异常的 tau 磷酸化。此外，AK1 的神经表达会缩短 tau 转基因文件的寿命。总之，这些观察结果表明 AK1 的神经元表达由 A(42) 诱导，通过 AMPK-GSK3 增加异常 tau 磷酸化，并有助于 tau 介导的神经变性，为 tau 病理磷酸化提供新的 GSK3 上游调节剂。
Abnormally hyperphosphorylated tau is often caused by tau kinases, such as GSK3 and Cdk5. Such occurrence leads to neurofibrillary tangle formation and neuronal degeneration in tauopathy, including Alzheimers disease (AD). However, little is known about the signaling cascade underlying the pathologic phosphorylation of tau by A(42). In this study, we show that adenylate kinase 1 (AK1) is a novel regulator of abnormal tau phosphorylation. AK1 expression is markedly increased in the brains of AD patients and AD model mice and is significantly induced by A(42) in the primary neurons. Ectopic expression of AK1 alone augments the pathologic phosphorylation of tau at PHF1, CP13 and AT180 epitopes and enhances the formation of tau aggregates. Inversely, downregulation of AK1 alleviates A(42)-induced hyperphosphorylation of tau. AK1 plays a role in A(42)-induced impairment of AMPK activity and GSK3 activation in the primary neurons. Pharmacologic studies show that treatment with an AMPK inhibitor activates GSK3, and a GSK3 inhibitor attenuates AK1-mediated tau phosphorylation. In a Drosophila model of human tauopathy, the retinal expression of human AK1 severely exacerbates rough eye phenotype and increases abnormal tau phosphorylation. Further, neural expression of AK1 reduces the lifespan of tau transgenic files. Taken together, these observations indicate that the neuronal expression of AK1 is induced by A(42) to increase abnormal tau phosphorylation via AMPK-GSK3 and contributes to tau-mediated neurodegeneration, providing a new upstream modulator of GSK3 in the pathologic phosphorylation of tau.