Good P F, Werner P, Hsu A, Olanow C W, Perl D P
Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA.
Am J Pathol. 1996 Jul;149(1):21-8.
Oxidative stress has been proposed as a pathogenetic mechanism in Alzheimer's disease. One mechanism of oxidative damage is the nitration of tyrosine residues in proteins, mediated by peroxynitrite breakdown. Peroxynitrite, a reaction product of nitric oxide and superoxide radicals, has been implicated in N-methyl-D-aspartate receptor-mediated excitotoxic damage. Reported evidence of oxidative stress in Alzheimer's disease includes increased iron, alterations in protective enzymes, and markers of oxidative damage to proteins and lipids. In this report, we demonstrate the presence of nitrotyrosine in neurofibrillary tangles of Alzheimer's disease. Nitrotyrosine was not detected in controls lacking neurofibrillary tangles. Immunolabeling was demonstrated to be specific nitrotyrosine in a series of control experiments. These observations link oxidative stress with a key pathological lesion of Alzheimer's disease, the neurofibrillary tangle, and demonstrate a pathogenetic mechanism in common with the other major neurodegenerative diseases of aging, Parkinson's disease and amyotrophic lateral sclerosis. These findings further implicate nitric oxide expression and excitotoxicity in the pathogenesis of cell death in Alzheimer's disease.
氧化应激被认为是阿尔茨海默病的一种发病机制。氧化损伤的一种机制是蛋白质中酪氨酸残基的硝化作用，由过氧亚硝酸盐分解介导。过氧亚硝酸盐是一氧化氮和超氧自由基的反应产物，与N-甲基-D-天冬氨酸受体介导的兴奋性毒性损伤有关。阿尔茨海默病中氧化应激的报道证据包括铁含量增加、保护酶的改变以及蛋白质和脂质氧化损伤的标志物。在本报告中，我们证明了阿尔茨海默病神经纤维缠结中存在硝基酪氨酸。在没有神经纤维缠结的对照中未检测到硝基酪氨酸。在一系列对照实验中，免疫标记被证明是特异性硝基酪氨酸。这些观察结果将氧化应激与阿尔茨海默病的一个关键病理病变——神经纤维缠结联系起来，并证明了与其他主要的衰老神经退行性疾病——帕金森病和肌萎缩侧索硬化症相同的发病机制。这些发现进一步表明一氧化氮表达和兴奋性毒性在阿尔茨海默病细胞死亡的发病机制中起作用。
