Differential expression of phosphorylated translation initiation factor 2 alpha in Alzheimer's disease and Creutzfeldt-Jakob's disease
Differential expression of phosphorylated translation initiation factor 2 alpha in Alzheimer's disease and Creutzfeldt-Jakob's disease
复制标题
DOI：
10.1046/j.1365-2990.2002.t01-1-00410.x
复制
发表时间：
2002-12-01
影响因子：
5
通讯作者：
Ferrer, I
中科院分区：
文献类型：
--
作者：
Ferrer, I
体外研究表明，磷酸化翻译起始因子 2α (TIF 2α) 可能具有多种功能，包括调节蛋白质合成、控制细胞死亡以及获得神经细胞对氧化应激的抵抗力。这些特性可能对某些人类神经退行性疾病有影响，例如阿尔茨海默病（AD）和克雅氏病（CJD），其中氧化应激似乎参与神经退行性和神经元死亡的过程。对 10 名 AD 患者（Braak 和 Braak 的 III 期和 VI 期）的死后样本进行了磷酸化 TIF 2α、磷酸化 SAPK/JNK、磷酸化 p38、tau、Cu/Zn 超氧化物歧化酶 1 (SOD 1) 和裂解 caspase-3 (17 kDa) 的单标记和双标记免疫组织化学，以及核 DNA 片段的原位末端标记。 7 名克雅氏病患者（5 例在 PrP 基因密码子 129 处存在蛋氨酸/蛋氨酸，2 例在密码子 129 处存在蛋氨酸/缬氨酸）和 8 名年龄匹配的对照。在对照大脑中未发现磷酸化 TIF 2α 免疫反应性，但在 AD 的海马、内嗅皮层和异皮质中具有神经原纤维缠结 (NFT) 或前缠结的神经元亚群中观察到强烈的磷酸化 TIF 2α 表达。磷酸化 TIF 2α 仅限于具有异常 tau 沉积的神经元，但只有约 80% 在海马中具有 NFT 的神经元和 60% 在异皮质中共定位有磷酸化 TIF 2α，因此表明并非所有具有 NFT 的神经元都过度表达磷酸化 TIF 2α。此外，在表达磷酸化 SAPK/JNK 和 p38 的神经元中发现了磷酸化 TIF 2α 免疫反应性，而这些神经元又参与 AD 中的 tau 磷酸化。然而，含有异常 tau 并表达 SOD 1 的老年斑营养不良性神经突对抗磷酸化 TIF 2α 抗体呈阴性。受淀粉样血管病影响的血管中的平滑肌细胞是 βA4 淀粉样蛋白衍生的氧化应激的假定目标，与磷酸化 TIF 2α 免疫反应性无关。使用核 DNA 片段原位末端标记方法进行的双重染色表明，磷酸化 TIF 2α 表达与单个细胞中核 DNA 脆弱性增加之间没有关系。此外，AD 中没有单个 caspase-3 免疫反应性细胞表达磷酸化 TIF 2α。氧化应激反应在伯格曼神经胶质细胞和一些反应性星形胶质细胞中表现为 SOD 1 阳性表达，已在克雅氏病中得到证实。在这些病例中未观察到磷酸化 SAPK/JNK 或磷酸化 p38 激酶免疫反应性。此外，克雅氏病中的神经元和神经胶质细胞不会过度表达磷酸化 TIF 2α。目前的结果表明，磷酸化 TIF 2α 在 tau 沉积异常的神经细胞亚群中选择性表达，并表明与 tau 沉积相关的因子在 AD 中对氧化应激敏感的某些神经元中的 TIF 2α 磷酸化过程中调节蛋白质合成。
Studies in vitro have shown that phosphorylated translation initiation factor 2alpha (TIF 2alpha) may have several functions, including regulation of protein synthesis, control of cell death and procurement of resistance to oxidative stress in nerve cells. These properties may have implications in certain human neurodegenerative diseases, such as Alzheimer's disease (AD) and Creutzfeldt-Jakob's disease (CJD), in which oxidative stress appears to be involved in the process of neurodegeneration and neurone death. Single and double-labelling immunohistochemistry to phosphorylated TIF 2alpha, phosphorylated SAPK/JNK, phosphorylated p38, tau, Cu/Zn superoxide dismutase 1 (SOD 1) and cleaved caspase-3 (17 kDa), and in situ end-labelling of nuclear DNA fragmentation, was carried out in postmortem samples of 10 patients with AD (stages III and VI of Braak and Braak), seven patients with CJD (five cases with methionine/methionine and two cases with methionine/valine at the codon 129 of the PrP gene) and eight age-matched controls. No phosphorylated TIF 2alpha immunoreactivity was found in control brains, but strong phosphorylated TIF 2alpha expression was observed in subpopulations of neurones bearing neurofibrillary tangles (NFTs) or pretangles in the hippocampus, entorhinal cortex and isocortex in AD. Phosphorylated TIF 2alpha is restricted to neurones with abnormal tau deposition, but only approximately 80% of neurones with NFTs in the hippocampus and 60% in the isocortex colocalize phosphorylated TIF 2alpha, thus indicating that not all neurones with NFTs over-express phosphorylated TIF 2alpha. Moreover, phosphorylated TIF 2alpha immunoreactivity was found in a percentage of neurones expressing phosphorylated SAPK/ JNK and p38, which, in turn, are involved in tau phosphorylation in AD. However, dystrophic neurites of senile plaques that contain abnormal tau and express SOD 1 are negative to antiphosphorylated TIF 2alpha antibodies. Smooth muscle cells in blood vessels affected by amyloid angiopathy, which are putative targets of betaA4 amyloid-derived oxidative stress, are not associated with phosphorylated TIF 2alpha immunoreactivity. Double-staining with the method of in situ end-labelling of nuclear DNA fragmentation demonstrated no relationship between phosphorylated TIF 2alpha expression and increased nuclear DNA vulnerability in individual cells. Moreover, no single caspase-3-immunoreactive cell in AD expressed phosphorylated TIF 2alpha. Oxidative stress response, manifested as positive SOD 1 expression in Bergmann glia and in a few reactive astrocytes, has been demonstrated in CJD. No phosphorylated SAPK/ JNK or phosphorylated p38 kinase immunoreactivity was observed in these cases. Moreover, neurones and glial cells do not over-express phosphorylated TIF 2alpha in CJD. The present results demonstrate selective expression of phosphorylated TIF 2alpha in subpopulations of nerve cells with abnormal tau deposition, and suggest that factors linked with tau deposition regulate protein synthesis throughout TIF 2alpha phosphorylation in certain neurones sensitive to oxidative stress in AD.