Aberrant expression of NOS isoforms in Alzheimer's disease is structurally related to nitrotyrosine formation
Aberrant expression of NOS isoforms in Alzheimer's disease is structurally related to nitrotyrosine formation
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DOI：
10.1016/s0006-8993(02)03280-8
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发表时间：
2002-10-25
期刊：
影响因子：
2.9
通讯作者：
Arendt, T
中科院分区：
文献类型：
--
作者：
Lüth, HJ;Münch, G;Arendt, T
一氧化氮（NO）生成酶一氧化氮合酶（NOS）的各种异构体在阿尔茨海默病（AD）中升高，表明NO在病理机制中的关键作用。NO可以与超氧化物反应生成过氧亚硝酸盐，这一过程被称为氧化应激，这可能在AD中发挥作用。过氧亚硝酸盐反过来又将酪氨酸残基硝酸化，形成硝基酪氨酸，其可以通过化学方法鉴定。为了研究AD患者NO合成增加与硝基酪氨酸沉积之间的潜在结构联系，我们分析了AD患者和对照组脑组织中神经元型NOS（nNOS）、诱导型NOS（iNOS）和内皮型NOS（eNOS）的表达，并比较了硝基酪氨酸的定位和分布。AD患者神经元、星形胶质细胞和血管中均检测到硝基酪氨酸。皮质锥体细胞中nNOS的异常表达与硝基酪氨酸高度共定位。此外，iNOS和eNOS在AD的星形胶质细胞中呈高表达。此外，双重免疫标记研究表明，在这些神经胶质细胞中，iNOS和eNOS与硝基酪氨酸共定位。因此，这表明，所有的NOS亚型在星形胶质细胞和神经元中的表达增加有助于过氧亚硝酸盐的合成，导致硝基酪氨酸的产生。鉴于广泛的亚型特异性NOS抑制剂，确定AD中形成过氧亚硝酸盐的最负责任的NOS亚型在治疗阿尔茨海默病中可能具有治疗重要性。(C)2002 Elsevier Science B.V.保留所有权利。
Various isoforms of the nitric oxide (NO) producing enzyme nitric oxide synthase (NOS) are elevated in Alzheimer's disease (AD) indicating a critical role for NO in the pathomechanism. NO can react with superoxide to generate peroxynitrite, a process referred to as oxidative stress, which is likely to play a role in AD. Peroxynitrite in turn, nitrates tyrosine residues to form nitrotyrosine which can be identified immunohistochemically. To study the potential structural link between the increased synthesis of NO and the deposition of nitrotyrosine in AD, we analyzed the expression of neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) in AD and control brain, and compared the localization with the distribution of nitrotyrosine. Nitrotyrosine was detected in neurons, astrocytes and blood vessels in AD cases. Aberrant expression of nNOS in cortical pyramidal cells was highly co-localized with nitrotyrosine. Furthermore, iNOS and eNOS were highly expressed in astrocytes in AD. In addition, double immunolabeling studies revealed that in these glial cells iNOS and eNOS are co-localized with nitrotyrosine. Therefore, it is suggested that increased expression of all NOS isoforms in astrocytes and neurons contributes to the synthesis of peroxynitrite which leads to generation of nitrotyrosine. In view of the wide range of isoform-specific NOS inhibitors, the determination of the most responsible isoform of NOS for the formation of peroxynitrite in AD could be of therapeutic importance in the treatment of Alzheimer's disease. (C) 2002 Elsevier Science B.V. All rights reserved.