Mislocalization of neuronal tau in the absence of tangle pathology in phosphomutant tau knockin mice
Mislocalization of neuronal tau in the absence of tangle pathology in phosphomutant tau knockin mice
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DOI：
10.1016/j.neurobiolaging.2015.11.028
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发表时间：
2016-03-01
影响因子：
4.2
通讯作者：
Coleman, Michael P.
中科院分区：
文献类型：
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作者：
Gilley, Jonathan;Ando, Kunie;Coleman, Michael P.
微管相关蛋白tau的过度磷酸化和纤维聚集是阿尔茨海默病和其他tau病的关键特征。为了研究tau磷酸化在病理过程中的作用，我们产生了一对互补的磷酸化蛋白tau敲入小鼠系。在富含脯氨酸和第一微管结合结构域的丝氨酸和/或苏氨酸残基上，有18个谷氨酸取代的拟磷蛋白只表达模拟过度磷酸化，而其磷酸化缺陷的对应物则具有匹配的丙氨酸取代。与预期的真正磷酸化效应一致，在体内，拟磷tau与微管和神经元膜的关联被严重破坏，而磷酸化缺陷突变的影响更有限或没有影响。然而，令人惊讶的是，年龄相关的tau错误定位在两种细胞系中都很明显，尽管在拟磷tau敲蛋白中重新分配似乎更广泛和更明显。尽管有这些变化，我们没有发现生化或免疫组织学证据表明病理性tau聚集在至少2岁的小鼠中。这些发现提出了关于tau磷酸化在驱动人类tau病变病理中的作用的重要问题。(C) 2016年作者。Elsevier Inc.出版。
Hyperphosphorylation and fibrillar aggregation of the microtubule-associated protein tau are key features of Alzheimer's disease and other tauopathies. To investigate the involvement of tau phosphorylation in the pathological process, we generated a pair of complementary phosphomutant tau knockin mouse lines. One exclusively expresses phosphomimetic tau with 18 glutamate substitutions at serine and/or threonine residues in the proline-rich and first microtubule-binding domains to model hyperphosphorylation, whereas its phosphodefective counterpart has matched alanine substitutions. Consistent with expected effects of genuine phosphorylation, association of the phosphomimetic tau with microtubules and neuronal membranes is severely disrupted in vivo, whereas the phosphodefective mutations have more limited or no effect. Surprisingly, however, age-related mislocalization of tau is evident in both lines, although redistribution appears more widespread and more pronounced in the phosphomimetic tau knockin. Despite these changes, we found no biochemical or immunohistological evidence of pathological tau aggregation in mice of either line up to at least 2 years of age. These findings raise important questions about the role of tau phosphorylation in driving pathology in human tauopathies. (C) 2016 The Authors. Published by Elsevier Inc.