Redox-active metals, oxidative stress, and Alzheimer's disease pathology
Redox-active metals, oxidative stress, and Alzheimer's disease pathology
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DOI：
10.1196/annals.1306.012
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Rogers, JT
中科院分区：
文献类型：
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作者：
Huang, XD;Moir, RD;Rogers, JT
大量证据表明，氧化还原活性的生物金属，铜和铁，以及氧化应激的稳态失调有助于阿尔茨海默病（AD）的神经病理学。目前的数据表明，金属可以直接与A β肽相互作用，A β肽是AD中的主要病变之一的β-淀粉样蛋白的主要成分。金属与Abeta的结合调节Abeta的几种理化性质，这些理化性质被认为是肽的致病性的核心。首先，我们和其他人已经表明，金属可以促进体外聚集成着色的A β淀粉样蛋白。研究已经证实，不溶性淀粉样斑块在AD死后的大脑异常富集铜，铁，锌。相反，金属螯合剂溶解这些蛋白质沉积物从死后AD脑组织和衰减大脑A β淀粉样蛋白负荷在APP转基因小鼠模型的AD。第二，我们已经证明，氧化还原活性铜（II），并在较小程度上，铁（III）的存在下，Abeta与伴随生产的活性氧（ROS），过氧化氢（H2 O2）和羟基自由基（OH.）减少。这些Abeta/金属氧化还原反应，这是沉默的氧化还原惰性锌（II），但加剧了生物还原剂，可能会直接导致广泛的氧化损伤AD大脑中观察到的。此外，研究还表明，H2 O2介导Abeta细胞毒性，并增加Abeta和淀粉样前体蛋白（APP）的产生。第三，APP mRNA的5'非翻译区（5' UTR）具有功能性铁反应元件（IRE），这与APP是氧化还原活性金属蛋白的生化证据一致。因此，Abeta、APP和金属之间的氧化还原相互作用可能是病理性正反馈系统的核心，其中Abeta淀粉样变性和氧化应激相互促进。氧化还原活性金属作为AD发病机制中的关键参与者的出现有力地表明，淀粉样蛋白特异性金属络合剂和抗氧化剂可以作为治疗这种可怕疾病的疾病修饰剂进行研究。
Considerable evidence is mounting that dyshomeostasis of the redox-active biometals, Cu and Fe, and oxidative stress contribute to the neuropathology of Alzheimer's disease (AD). Present data suggest that metals can interact directly with Abeta peptide, the principal component of beta-amyloid that is one of the primary lesions in AD. The binding of metals to Abeta modulates several physiochemical properties of Abeta that are thought to be central to the pathogenicity of the peptide. First, We and others have shown that metals can promote the in vitro aggregation into tinctorial Abeta amyloid. Studies have confirmed that insoluble amyloid plaques in postmortem AD brain are abnormally enriched in Cu, Fe, and Zn. Conversely, metal chelators dissolve these proteinaceous deposits from postmortem AD brain tissue and attenuate cerebral Abeta amyloid burden in APP transgenic mouse models of AD. Second, we have demonstrated that redox-active Cu(II) and, to a lesser extent, Fe(III) are reduced in the presence of Abeta with concomitant production of reactive oxygen species (ROS), hydrogen peroxide (H2O2) and hydroxyl radical (OH.). These Abeta/metal redox reactions, which are silenced by redox-inert Zn(II), but exacerbated by biological reducing agents, may lead directly to the widespread oxidation damages observed in AD brains. Moreover, studies have also shown that H2O2 mediates Abeta cellular toxicity and increases the production of both Abeta and amyloid precursor protein (APP). Third, the 5' untranslated region (5'UTR) of APP mRNA has a functional iron-response element (IRE), which is consistent with biochemical evidence that APP is a redox-active metalloprotein. Hence, the redox interactions between Abeta, APP, and metals may be at the heart of a pathological positive feedback system wherein Abeta amyloidosis and oxidative stress promote each other. The emergence of redox-active metals as key players in AD pathogenesis strongly argues that amyloid-specific metal-complexing agents and antioxidants be investigated as possible disease-modifying agents for treating this horrible disease.