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Fenton chemistry and oxidative stress mediate the toxicity of the β‐amyloid peptide in a Drosophila model of Alzheimer’s disease
Author(s) -
Rival Thomas,
Page Richard M.,
Chandraratna Dhianjali S.,
Sendall Timothy J.,
Ryder Edward,
Liu Beinan,
Lewis Huw,
Rosahl Thomas,
Hider Robert,
Camargo L. M.,
Shearman Mark S.,
Crowther Damian C.,
Lomas David A.
Publication year - 2009
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2009.06701.x
Subject(s) - oxidative stress , reactive oxygen species , ferritin , chemistry , toxicity , biochemistry , amyloid (mycology) , oxidative phosphorylation , pharmacology , microbiology and biotechnology , biology , inorganic chemistry , organic chemistry
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 (Aβ 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 H 2 O 2 scavenger catalase are the most potent suppressors of the toxicity of wild‐type and Arctic (E22G) Aβ 1–42 . Likewise, treatment with the iron‐binding compound clioquinol increased the lifespan of flies expressing Arctic Aβ 1–42 . The effect of iron appears to be mediated by oxidative stress as ferritin heavy chain co‐expression reduced carbonyl levels in Aβ 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 Aβ 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 Aβ 1–42 toxicity in vivo and provide strong support for Alzheimer’s disease therapies based on metal chelation.