Fenton chemistry and oxidative stress mediate the toxicity of the ß-amyloid peptide in a Drosophila model of Alzheimer's disease.

Rival, R., Page, R.M., Chandraratna, D.S., Sendall, T.J., Ryder, E., Liu, B., Lewis, H., Rosahl, T., Hider, R., Camargo, L.M., Shearman, M.S., Crowther, D.C., Lomas, D.A.
Journal   Eur J Nuroscience.
Species  
Analytes Measured   Abeta 42
Matrix Tested   Drosophila brain extracts
Year   2009
Volume   29
Page Numbers   1335-1347
Application   Alzheimers
Abstract
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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