Fenton chemistry and oxidative stress mediate the toxicity of the beta-amyloid peptide in a Drosophila model of Alzheimer's disease.
Fenton chemistry and oxidative stress mediate the toxicity of the beta-amyloid peptide in a Drosophila model of Alzheimer's disease.
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DOI：
10.1111/j.1460-9568.2009.06701.x
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发表时间：
2009-04
期刊：
影响因子：
--
通讯作者：
Lomas DA
中科院分区：
文献类型：
--
作者：
Rival T;Page RM;Chandraratna DS;Sendall TJ;Ryder E;Liu B;Lewis H;Rosahl T;Hider R;Camargo LM;Shearman MS;Crowther DC;Lomas DA
β-淀粉样肽（Aβ）聚集体介导其毒性的机制尚不确定。我们在此发现，在阿尔茨海默病的果蝇模型中，42个氨基酸的Aβ亚型（Aβ1-42）的表达改变了参与氧化应激的基因的表达。随后的遗传筛选证实了氧化应激的重要性，并对活性氧物质细胞代谢步骤进行了分子剖析，结果表明铁结合蛋白铁蛋白和H2 O2清除剂过氧化氢酶是野生型和北极型毒性的最有效抑制剂（E22 G）Aβ1-42。同样，用铁结合化合物氯碘羟喹治疗增加了表达Arctic Aβ1-42的果蝇的寿命。铁的作用似乎是由氧化应激介导的，因为铁蛋白重链共表达使Aβ1-42果蝇中的羰基水平降低了65%，并使存活和运动功能恢复正常。尽管Aβ1-42水平升高，但仍实现了这一目标。综上所述，我们的数据表明，氧化应激，可能是由羟基自由基介导的，并产生的芬顿反应，是必不可少的Aβ1-42在体内的毒性，并提供了强有力的支持阿尔茨海默病的治疗方法的基础上，金属螯合。
The mechanism by which aggregates of the β-amyloid peptide (Aβ) mediate their toxicity is uncertain. We show here that the expression of the 42-amino-acid isoform of Aβ (Aβ1–42) changes the expression of genes involved in oxidative stress in a Drosophila model of Alzheimer’s disease. A subsequent genetic screen confirmed the importance of oxidative stress and a molecular dissection of the steps in the cellular metabolism of reactive oxygen species revealed that the iron-binding protein ferritin and the H2O2 scavenger catalase are the most potent suppressors of the toxicity of wild-type and Arctic (E22G) Aβ1–42. Likewise, treatment with the iron-binding compound clioquinol increased the lifespan of flies expressing Arctic Aβ1–42. The effect of iron appears to be mediated by oxidative stress as ferritin heavy chain co-expression reduced carbonyl levels in Aβ1–42 flies by 65% and restored the survival and locomotion function to normal. This was achieved despite the presence of elevated levels of the Aβ1–42. Taken together, our data show that oxidative stress, probably mediated by the hydroxyl radical and generated by the Fenton reaction, is essential for Aβ1–42 toxicity in vivo and provide strong support for Alzheimer’s disease therapies based on metal chelation.
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