Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
J Neurochem. 2008 Jun 1;105(6):2098-108. doi: 10.1111/j.1471-4159.2008.05294.x.
The microtubule-associated protein tau is abnormally hyperphosphorylated in the brains of individuals with Alzheimer disease and other tauopathies, and is believed to play a critical role in the pathogenesis of these diseases. While the mechanisms leading to abnormal tau phosphorylation remain elusive, the recent demonstration of reversible tau phosphorylation during hibernation provides an ideal physiological model to study this critical process in vivo. In this study, Arctic ground squirrels (AGS) during hibernation were used to study mechanisms related to tau hyperphosphorylation. Our data demonstrate that tau is hyperphosphorylated at all six sites (S199, T205, S214, S262, S396, and S404) examined in hibernating AGS. Interestingly, only three of these sites (S199, S262, and S404) are dephosphorylated in aroused animals, suggesting a reversible phosphorylation at selective sites. Summer-active AGS demonstrated the lowest tau phosphorylation at all these sites. To explore the mechanisms underlying increased tau phosphorylation during hibernation, the expression level and enzyme activity of various potential tau kinases and protein phosphatases were examined. The kinetic analysis of enzyme activity at different temperatures revealed differential changes in enzyme activity with temperature decline. Specifically, increased protein kinase A activity, decreased protein phosphatase 2A activity, as well as substantial contribution from glycogen synthase kinase-3beta, likely play a key role in increased tau phosphorylation during hibernation in AGS.
微管相关蛋白 tau 在阿尔茨海默病和其他神经tau 病变患者的大脑中异常过度磷酸化，被认为在这些疾病的发病机制中起关键作用。虽然导致异常 tau 磷酸化的机制仍不清楚，但最近在冬眠期间发现 tau 磷酸化可逆，为在体内研究这一关键过程提供了理想的生理模型。在这项研究中，使用冬眠的北极地松鼠（AGS）来研究与 tau 过度磷酸化相关的机制。我们的数据表明，tau 在所有六个被检查的位点（S199、T205、S214、S262、S396 和 S404）都发生过度磷酸化。有趣的是，只有这三个位点（S199、S262 和 S404）在唤醒的动物中去磷酸化，这表明选择性位点的磷酸化是可逆的。夏季活跃的 AGS 在所有这些位点的 tau 磷酸化程度最低。为了探讨冬眠期间 tau 过度磷酸化的潜在机制，我们研究了各种潜在 tau 激酶和蛋白磷酸酶的表达水平和酶活性。在不同温度下的酶活性动力学分析揭示了酶活性随温度下降的差异变化。具体而言，蛋白激酶 A 活性的增加、蛋白磷酸酶 2A 活性的降低以及糖原合酶激酶-3β的大量贡献，可能在 AGS 冬眠期间 tau 过度磷酸化中起关键作用。
