Nitrosative stress, cellular stress response, and thiol homeostasis in patients with Alzheimer's disease
Nitrosative stress, cellular stress response, and thiol homeostasis in patients with Alzheimer's disease
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DOI：
10.1089/ars.2006.8.1975
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发表时间：
2006-11-01
影响因子：
6.6
通讯作者：
Butterfield, D. A.
中科院分区：
文献类型：
--
作者：
Calabrese, Vittorio;Sultana, Rukhsana;Butterfield, D. A.
阿尔茨海默病（Alzheimer's disease，AD）是一种以认知和记忆衰退、人格改变和突触丧失为特征的神经退行性疾病。越来越多的证据表明，因素，如氧化和亚硝化应激，谷胱甘肽耗竭，和受损的蛋白质代谢可以相互作用的恶性循环，这是中央AD发病机制。在本研究中，我们证明了AD患者的大脑经历了氧化变化，这与所谓的维生素的强烈诱导有关，包括热休克蛋白（HSP）血红素加氧酶-1（HO-1）、HSP 60和HSP 72，以及硫氧还蛋白还原酶（TRXr）。在AD患者的下顶叶脑中，观察到HO-1和TRXr的表达显著增加，而HO-2的表达降低，与对照组相比。AD小脑TRHr无明显升高。与对照组相比，AD患者的血浆GSH降低，并且与氧化应激标志物（即，GSSG、羟基壬烯醛、蛋白质羰基含量和硝基酪氨酸）。在AD淋巴细胞中，我们观察到诱导型一氧化氮合酶、HO-1、HSP 72、HSP 60和TRXr的表达增加。我们的数据支持硝化应激在AD发病机制中的作用，并表明应激反应基因，如HO-I和TRXr，可能是新的细胞保护策略的重要靶点。
Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive and memory decline, personality changes, and synapse loss. Increasing evidence indicates that factors such as oxidative and nitrosative stress, glutathione depletion, and impaired protein metabolism can interact in a vicious cycle, which is central to AD pathogenesis. In the present study, we demonstrate that brains of AD patients undergo oxidative changes classically associated with a strong induction of the so-called vitagenes, including the heat shock proteins (HSPs) heme oxygenase-1 (HO-1), HSP60, and HSP72, as well as thioredoxin reductase (TRXr). In inferior parietal brain of AD patients, a significant increase in the expression of HO-1 and TRXr was observed, whereas HO-2 expression was decreased, compared with controls. TRHr was not increased in AD cerebellum. Plasma GSH was decreased in AD patients, compared with the control group, and was associated with a significant increase in oxidative stress markers (i.e., GSSG, hydroxynonenal, protein carbonyl content, and nitrotyrosine). In AD lymphocytes, we observed an increased expression of inducible nitric oxide synthase, HO-1, Hsp72, HSP60, and TRXr. Our data support a role for nitrative stress in the pathogenesis of AD and indicate that the stress-responsive genes, such as HO-I and TRXr, may represent important targets for novel cytoprotective strategies.