EXPRESSION OF HEME OXYGENASE-1 IN THE SENESCENT AND ALZHEIMER-DISEASED BRAIN
EXPRESSION OF HEME OXYGENASE-1 IN THE SENESCENT AND ALZHEIMER-DISEASED BRAIN
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DOI：
10.1002/ana.410370609
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发表时间：
1995-06-01
影响因子：
11.2
通讯作者：
STOPA, EG
中科院分区：
文献类型：
--
作者：
SCHIPPER, HM;STOPA, EG
血红素氧合酶-1是一种细胞应激蛋白，在脑和其他组织中表达，以响应氧化挑战和其他有害刺激。使用免疫组织化学和免疫荧光标记结合激光扫描共聚焦显微镜，我们观察到强烈的血红素氧合酶-1的免疫反应性的海马和颞叶皮层的阿尔茨海默病（AD）的大脑相对于年龄匹配的对照标本的神经元。此外，我们证明了血红素加氧酶-1在AD标本中与胶质细胞酸性蛋白阳性星形胶质细胞、神经纤维缠结和老年斑的一致共定位。在AD海马中，大约86%的胶质细胞酸性蛋白阳性星形胶质细胞表达血红素加氧酶-1，而在正常衰老对照标本中，只有6.8%的海马星形胶质细胞表达血红素加氧酶-1（p < 0.0001）。在海马和新皮质以外的区域，如黑质，实验组中表达血红素氧合酶-1的星形胶质细胞比例（12.8%）与对照组（6.4%，p > 0.05）无显著差异。十二烷基硫酸钠-聚丙烯酰胺凝胶电泳后，来自AD颞叶皮层和海马的蛋白质提取物的蛋白质印迹法观察到对应于血红素加氧酶-1的32-kd条带。血红素加氧酶-1条带在对照标本制备的蛋白质提取物中非常微弱或不存在。这些结果表明，血红素氧合酶-1显着过表达的神经元和星形胶质细胞的AD海马和大脑皮层相对于对照组的大脑。血红素氧合酶-1在AD脑中的上调支持受影响的组织正在经历慢性氧化应激的论点。此外，血红素降解代谢产物一氧化碳的过量产生可能参与了AD的发病机制。
Heme oxygenase-1 is a cellular stress protein expressed in brain and other tissues in response to oxidative challenge and other noxious stimuli. Using immunohistochemistry and immunofluorescent labeling in conjunction with laser scanning confocal microscopy, we observed intense immunoreactivity of heme oxygenase-1 in neurons of the hippocampus and temporal cortex of Alzheimer-diseased (AD) brain relative to age-matched control specimens. Furthermore, we demonstrated consistent colocalization of heme oxygenase-1 to glial fibrillary acidic protein-positive astrocytes, neurofibrillary tangles, and senile plaques in the AD specimens. In AD hippocampus, approximately 86% of glial fibrillary acidic protein-positive astrocytes-expressed heme oxygenase-1, whereas only 6.8% of hippocampal astrocytes in normal senescent control specimens were immunopositive for heme oxygenase-1 (p < 0.0001). In regions other than the hippocampus and neocortex, such as the substantia nigra, the proportion of astrocytes expressing heme oxygenase-1 in the experimental group (12.8%) was not significantly different from that in the controls (6.4%, p > 0.05). Robust 32-kd bands corresponding to heme oxygenase-1 were observed by Western blotting of protein extracts derived from AD temporal cortex and hippocampus after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Heme oxygenase-1 bands were very faint or absent in protein extracts prepared from control specimens. These results indicate that heme oxygenase-1 is significantly overexpressed in neurons and astrocytes of AD hippocampus and cerebral cortex relative to control brains. Upregulation of heme oxygenase-1 in AD brain supports the contention that the affected tissues are experiencing chronic oxidative stress. In addition, the excessive generation of carbon monoxide, a metabolite of heme degradation, may participate in the pathogenesis of AD.