Tyrosine Nitration within the Pro line-Rich Region of Tau in Alzheimer's Disease
Tyrosine Nitration within the Pro line-Rich Region of Tau in Alzheimer's Disease
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DOI：
10.1016/j.ajpath.2011.01.030
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发表时间：
2011-05-01
影响因子：
6
通讯作者：
Binder, Lester I.
中科院分区：
文献类型：
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作者：
Reyes, Juan F.;Fu, Yifan;Binder, Lester I.
大量证据表明，硝化性损伤导致阿尔茨海默病(AD)和其他神经退行性疾病的神经退行性变。此前，我们在体外表明，在tau蛋白中，N末端的酪氨酸残基(Y18和Y29)比其他酪氨酸位点(Y197和Y394)更容易被硝化修饰。使用Y18和Y29硝化tau的位点特异性抗体，我们在神经胶质(Y18)和神经元(Y29)tau病理中都发现了tau的硝化。在这项研究中，我们报道了两种新的单抗Tau-nY197和Tau-nY394的特性，它们分别识别Y197和Y394硝化牛磺酸。通过Western印迹分析，Tau-nY197标记的可溶性tau和不溶的成对螺旋丝蛋白(phf-tau)在Y197处硝化。Tau-nY394不能标记从对照组或重症AD标本中分离出来的可溶性tau，但标记不溶性PHF-tau的程度有限。使用Tau-nY197的免疫组织化学分析显示与AD相关的标志性tau病理；Tau-nY394没有检测到任何该疾病特有的病理损害。这些数据表明，AD标志性病理包涵体的一部分含有Y197硝化的tau。然而，在所有对照样品，包括Braak阶段0的样品中，也发现了Y197的硝化作用，这表明在人脑中，在tau富含Pro区域的这个位置上的硝化作用可能具有正常的生物学功能。(Am J Pathol 2011,178：2275-2285；DOI：10.1016/j.ajpath.2011.01.030)
A substantial body of evidence suggests that nitrative Injury contributes to neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative disorders. Previously, we showed in vitro that within the tau protein the N-terminal tyrosine residues (Y18 and Y29) are more susceptible to nitrative modifications than other tyrosine sites (Y197 and Y394). Using site-specific antibodies to nitrated tau at Y18 and Y29, we identified tau nitrated in both glial (Y18) and neuronal (Y29) tau pathologies. In this study, we report the characterization of two novel monoclonal antibodies, Tau-nY197 and Tau-nY394, recognizing tau nitrated at Y197 and Y394, respectively. By Western blot analysis, Tau-nY197 labeled soluble tau and insoluble paired helical filament proteins (PHF-tau) nitrated at Y197 from control and AD brain samples. Tau-nY394 failed to label soluble tau isolated from control or severe AD samples, but labeled insoluble PHF-tau to a limited extent. Immunohistochemical analysis using Tau-nY197 revealed the hallmark tau pathology associated with AD; Tau-nY394 did not detect any pathological lesions characteristic of the disorder. These data suggest that a subset of the hallmark pathological inclusions of AD contain tau nitrated at Y197. However, nitration at Y197 was also identified in soluble tau from all control samples, including those at Braak stage 0, suggesting that nitration at this site in the proline-rich region of tau may have normal biological functions in the human brain. (Am J Pathol 2011, 178:2275-2285; DOI: 10.1016/j.ajpath.2011.01.030)