The unfolded protein response is activated in Alzheimer's disease
The unfolded protein response is activated in Alzheimer's disease
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DOI：
10.1007/s00401-005-1038-0
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发表时间：
2005-08-01
影响因子：
12.7
通讯作者：
Scheper, W
中科院分区：
文献类型：
--
作者：
Hoozemans, JJM;Veerhuis, R;Scheper, W
阿尔茨海默病（Alzheimer's disease，AD）是一种以错折叠蛋白质聚集和聚集为特征的神经病理学疾病。内质网（ER）中错误折叠蛋白的存在触发了称为未折叠蛋白反应（UPR）的细胞应激反应，可以保护细胞免受错误折叠蛋白的毒性积累。在这项研究中，我们调查了激活的UPR在AD。蛋白质水平的BiP/GRP 78，一个分子伴侣，这是在UPR期间上调，被发现增加在AD颞叶皮层和海马通过Western印迹分析确定。在免疫组化水平上，在AD中观察到BiP/GRP 78的强化染色，其不与AT 8阳性神经元缠结共定位。此外，我们进行了磷酸化（激活）胰腺ER激酶（p-PERK），一种在UPR过程中激活的ER激酶的免疫组织化学。在AD患者的神经元中观察到p-PERK，但在非痴呆对照病例中未观察到，并且未与AT 8阳性缠结共定位。总体而言，这些数据表明，UPR在AD中被激活，并且BiP/GRP 78和p-PERK在细胞学正常表现的神经元中的出现增加表明UPR在AD神经变性早期的作用。虽然UPR在AD发病机制中的最初参与可能是神经保护性的，但AD中UPR的持续激活可能引发或介导神经变性。
Alzheimer's disease (AD) is, at the neuropathological level, characterized by the accumulation and aggregation of misfolded proteins. The presence of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR) that may protect the cell against the toxic buildup of misfolded proteins. In this study we investigated the activation of the UPR in AD. Protein levels of BiP/GRP78, a molecular chaperone which is up-regulated during the UPR, was found to be increased in AD temporal cortex and hippocampus as determined by Western blot analysis. At the immunohistochemical level intensified staining of BiP/GRP78 was observed in AD, which did not co-localize with AT8-positive neurofibrillary tangles. In addition, we performed immunohistochemistry for phosphorylated (activated) pancreatic ER kinase (p-PERK), an ER kinase which is activated during the UPR. p-PERK was observed in neurons in AD patients, but not in non-demented control cases and did not co-localize with AT8-positive tangles. Overall, these data show that the UPR is activated in AD, and the increased occurrence of BiP/ GRP78 and p-PERK in cytologically normal-appearing neurons suggest a role for the UPR early in AD neurodegeneration. Although the initial participation of the UPR in AD pathogenesis might be neuroprotective, sustained activation of the UPR in AD might initiate or mediate neurodegeneration.