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首页> 外文期刊>The European Journal of Neuroscience >Terminal hypothermic Tau.P301L mice have increased Tau phosphorylation independently of glycogen synthase kinase 3α/β
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Terminal hypothermic Tau.P301L mice have increased Tau phosphorylation independently of glycogen synthase kinase 3α/β

机译:末端低温Tau.P301L小鼠独立于糖原合酶激酶3α/β的Tau磷酸化增加

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摘要

The microtubule-associated protein Tau is responsible for a large group of neurodegenerative disorders, known as tauopathies, including Alzheimer's disease. Tauopathy result from augmented and/or aberrant phosphorylation of Tau. Besides aging and various genetic and epigenetic defects that remain largely unknown, an important non-genetic agent that contributes is hypothermia, eventually caused by anesthesia. Remarkably, tauopathy in brains of hibernating mammals is not pathogenic, and, because it is fully reversible, is even considered to be neuroprotective. Here, we assessed the terminal phase of Tau.P301L mice and bigenic crosses with mice lacking glycogen synthase kinase 3 (GSK3)α completely, or GSK3β specifically in neurons. We also analysed biGT bigenic mice that co-express Tau.P301L with GSK3β.S9A and develop severe forebrain tauopathy with age. We found that the precocious mortality of Tau.P301L mice was typified by hypothermia that aggravated Tau phosphorylation, but, surprisingly, independently of GSK3α/β. The important contribution of hypothermia at the time of death of mice with tauopathy suggests that body temperature should be included as a parameter in the analysis of pre-clinical models, and, by extension, in patients suffering from tauopathy.
机译:与微管相关的蛋白Tau导致了一大批神经退行性疾病,包括牛津病,包括阿尔茨海默氏病。牛磺酸病是由于牛磺酸的磷酸化增加和/或异常引起的。除了衰老和各种遗传和表观遗传缺陷(仍然很大程度上未知)外,重要的非遗传因素是体温过低,最终是由麻醉引起的。值得注意的是,冬眠哺乳动物的大脑中的tauopathy不是致病的,而且由于它是完全可逆的,因此甚至被认为具有神经保护作用。在这里,我们评估了Tau.P301L小鼠的终末期以及与完全缺乏糖原合酶激酶3(GSK3)α或神经元中的GSK3β完全缺乏的小鼠的双基因杂交。我们还分析了BiGT双基因小鼠,它们与GSK3β.S9A共表达Tau.P301L,并随着年龄的增长而发展为严重的前脑部tauopathy。我们发现,Tau.P301L小鼠的早熟性死亡以体温过低为特征,该体温加重了Tau的磷酸化作用,但令人惊讶的是,与GSK3α/β无关。在患有tauopathy的小鼠死亡时,体温过低的重要贡献表明,体温应作为临床前模型的分析参数,并应包括在患有tauopathy的患者中作为参数。

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