The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies
The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies
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DOI：
10.1002/path.3969
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发表时间：
2012-04-01
影响因子：
7.3
通讯作者：
Hoozemans, Jeroen J. M.
中科院分区：
文献类型：
--
作者：
Nijholt, Diana A. T.;van Haastert, Elise S.;Hoozemans, Jeroen J. M.
未折叠蛋白反应（unfolded protein response，UPR）是内质网（endoplasmic reticulum，ER）内稳态紊乱时激活的一种应激反应。以前，我们报道了UPR的激活与阿尔茨海默病（AD）中磷酸化tau（p-tau）的存在密切相关。除了细胞内p-tau的存在增加之外，AD脑的特征在于β淀粉样蛋白（A β）的细胞外沉积。最近的体外研究表明，A β可以诱导ER应激和UPR的激活。本研究的目的是调查散发性tau蛋白病如进行性核上性麻痹（PSP）和皮克病（PiD）中的UPR激活，以及与17号染色体（FTDP-17）相关的额颞叶痴呆和帕金森综合征家族病例，这些病例携带编码tau蛋白（MAPT）的基因突变。在神经病理学定义为额颞叶变性伴tau病变（FTLD-tau）的病例中，通过免疫组织化学评估磷酸化胰腺ER激酶（pPERK）和磷酸化肌醇需要酶1a（pIRE 1）的存在，这表明UPR活化。在FTLD-tau病例的神经元和神经胶质中观察到UPR激活标志物pPERK和pIRE 1的存在增加，与tau病理学阴性的FTLD亚型或非神经学对照相反。pPERK和pIRE 1也在相对年轻的MAPT突变携带者中显著存在。在FTLD-tau病例的海马中观察到UPR活化标记物和p-tau的存在之间的强关联。FTLD-tau病例的双重免疫组织化学染色显示，UPR激活主要在显示p-tau弥漫性染色的神经元中观察到。这些数据表明，UPR活化与p-tau的积累和聚集密切相关，并且独立于A β沉积物发生。我们的研究结果提供了新的病理学见解之间的密切联系p-tau蛋白和UPR激活的tau蛋白病。版权所有（c）2012大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
The unfolded protein response (UPR) is a stress response activated upon disturbed homeostasis in the endoplasmic reticulum (ER). Previously, we reported that the activation of the UPR closely correlates with the presence of phosphorylated tau (p-tau) in Alzheimer's disease (AD). As well as increased presence of intracellular p-tau, AD brains are characterized by extracellular deposits of beta amyloid (A beta). Recent in vitro studies have shown that A beta can induce ER stress and activation of the UPR. The aim of the present study is to investigate UPR activation in sporadic tauopathies like progressive supranuclear palsy (PSP) and Pick's disease (PiD), and familial cases with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) which carry mutations in the gene encoding for tau (MAPT). The presence of phosphorylated pancreatic ER kinase (pPERK) and phosphorylated inositol requiring enzyme 1a (pIRE1), which are indicative of an activated UPR, was assessed by immunohistochemistry in cases neuropathologically defined as frontotemporal lobar degeneration with tau pathology (FTLD-tau). Increased presence of UPR activation markers pPERK and pIRE1 was observed in neurons and glia in FTLD-tau cases, in contrast to FTLD subtypes negative for tau pathology or in non-neurological controls. pPERK and pIRE1 were also prominently present in relatively young carriers of MAPT mutation. A strong association between the presence of UPR activation markers and p-tau was observed in the hippocampus of FTLD-tau cases. Double immunohistochemical staining on FTLD-tau cases revealed that UPR activation is predominantly observed in neurons that show diffuse staining of p-tau. These data demonstrate that UPR activation is intimately connected with the accumulation and aggregation of p-tau, and occurs independently from A beta deposits. Our findings provide new pathological insight into the close association between p-tau and UPR activation in tauopathies. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.