Kinase activities increase during the development of tauopathy in htau mice
Kinase activities increase during the development of tauopathy in htau mice
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DOI：
10.1111/j.1471-4159.2007.04930.x
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发表时间：
2007-12-01
影响因子：
4.7
通讯作者：
Noble, Wendy
中科院分区：
文献类型：
--
作者：
Kelleher, Ian;Garwood, Claire;Noble, Wendy
过度磷酸化的tau聚集体是神经元缠结的核心成分。最近的研究表明，缠结、神经变性和随后的记忆障碍之间存在差异，这增加了早期预聚集形式的tau可能有毒的可能性。为了进一步了解tau蛋白异常形式之间的关系，我们分析了在缠结形成转基因小鼠中tau蛋白病发展过程中tau蛋白的病理变化。此外，我们还定量了一组蛋白激酶内源性水平的变化。我们发现聚集的tau蛋白和疾病特异性构象变化逐渐增加，在特定位点以年龄依赖性方式发生过度磷酸化。特异性磷酸化改变与聚集的tau蛋白和异常tau蛋白构象的量之间存在显著相关性。在测试的蛋白激酶中，我们发现随着年龄的增长，在htau系中磷酸化（激活）p38和细胞周期蛋白依赖性激酶-5神经元激活剂p35和p25增加，但在非缠结形成对照小鼠中没有。tau激酶的变化与异常构象中存在的tau的量和htau小鼠中不溶性tau相关。这些数据表明，cdk 5和p38可能与tau蛋白病进行性发展过程中野生型人tau蛋白的病理变化有关。
Hyperphosphorylated tau aggregates are the core constituent of neurofibrillary tangles. Recent research has shown a division between the presence of tangles, neurodegeneration and subsequent memory impairment, raising the possibility that an earlier pre-aggregated form of tau may be toxic. To gain further insight into the relationship between abnormal forms of tau, we have analyzed pathological changes in tau during tauopathy development in tangle-forming transgenic mice. In addition, we have quantified changes in the endogenous levels of a panel of protein kinases. We show progressive increases in aggregated tau and disease-specific conformational change, with hyperphosphorylation occurring in an age-dependent manner at specific sites. There were significant correlations between specific phosphorylation changes and amounts of aggregated tau and and abnormal tau conformations. Of the protein kinases tested, we found increases in phosphorylated (activated) p38 and the cyclin-dependent kinase-5 neuronal activators, p35 and p25, with aging, in the htau line, but not in non-tangle-forming control mice. Changes in tau kinases correlated with the amount of tau present in abnormal conformations and with insoluble tau in htau mice. These data suggest that cdk5 and p38 may be associated with pathological changes in wild-type human tau during the progressive development of tauopathy.