Journal
EUROPEAN JOURNAL OF NEUROSCIENCE
Volume 29, Issue 7, Pages 1335-1347Publisher
WILEY
DOI: 10.1111/j.1460-9568.2009.06701.x
Keywords
aggregation; chelation therapy; hydroxy radical; iron
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Funding
- Wellcome Trust, Medical Research Council (UK)
- Papworth NHS Trust
- Medical Research Council [G0700990, G0500306] Funding Source: researchfish
- MRC [G0500306, G0700990] Funding Source: UKRI
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The mechanism by which aggregates of the beta-amyloid peptide (A beta) mediate their toxicity is uncertain. We show here that the expression of the 42-amino-acid isoform of A beta (A beta(1-42)) 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) A beta(1-42). Likewise, treatment with the iron-binding compound clioquinol increased the lifespan of flies expressing Arctic A beta(1-42). The effect of iron appears to be mediated by oxidative stress as ferritin heavy chain co-expression reduced carbonyl levels in A beta(1-42) flies by 65% and restored the survival and locomotion function to normal. This was achieved despite the presence of elevated levels of the A beta(1-42). Taken together, our data show that oxidative stress, probably mediated by the hydroxyl radical and generated by the Fenton reaction, is essential for A beta(1-42) toxicity in vivo and provide strong support for Alzheimer's disease therapies based on metal chelation.
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