The Aβ peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction
The Aβ peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction
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DOI：
10.1021/bi990438f
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发表时间：
1999-06-15
期刊：
影响因子：
2.9
通讯作者：
Bush, AI
中科院分区：
文献类型：
--
作者：
Huang, XD;Atwood, CS;Bush, AI
氧化应激标志物表征阿尔茨海默病和淀粉样蛋白转基因小鼠的神经病理学。淀粉样蛋白A β肽的神经毒性与细胞培养物中过氧化物的产生有关，其机制未知。我们现在表明，人类A β通过一种机制直接产生过氧化氢（H2 O2），该机制涉及金属离子Fe（III）或Cu（II）的还原，为芬顿型化学创造了条件。分光光度实验确定A β肽将Fe（III）和Cu（II）分别还原为Fe（II）和Cu（I）。光谱化学技术被用来表明，分子氧，然后被捕获的A β和还原为H2 O2的反应，是由亚化学计量的Fe（II）或Cu（I），在Cu（II）或Fe（III）的存在下，A β产生一个积极的硫代巴比妥反应物质（TEARS）测定，与羟基自由基（OH）的产生兼容。当由A β-42产生的还原金属和TEARS反应性的量远大于A β 1-40 >大鼠A β 1-40时，还原金属和TEARS反应性的量最大，这是与淀粉样蛋白病理学中天然肽的参与相关的化学关系。这些发现表明A β的积累可能是阿尔茨海默病中氧化应激的直接来源。
Oxidative stress markers characterize the neuropathology both of Alzheimer's disease and of amyloid-bearing transgenic mice. The neurotoxicity of amyloid A beta peptides has been linked to peroxide generation in cell cultures by an unknown mechanism. We now show that human A beta directly produces hydrogen peroxide (H2O2) by a mechanism that involves the reduction of metal ions, Fe(III) or Cu(II), setting up conditions for Fenton-type chemistry. Spectrophotometric experiments establish that the A beta peptide reduces Fe(III) and Cu(II) to Fe(II) and Cu(I), respectively. Spectrochemical techniques are used to show that molecular oxygen is then trapped by A beta and reduced to H2O2 in a reaction that is driven by substoichiometric amounts of Fe(II) or Cu(I), In the presence of Cu(II) or Fe(III), A beta produces a positive thiobarbituric-reactive substance (TEARS) assay, compatible with the generation of the hydroxyl radical (OH). The amounts of both reduced metal and TEARS reactivity are greatest when generated by A beta-42 much greater than A beta 1-40 > rat A beta 1-40, a chemical relationship that correlates with the participation of the native peptides in amyloid pathology, These findings indicate that the accumulation of A beta could be a direct source of oxidative stress in Alzheimer's disease.