title: Fenton chemistry and oxidative stress mediate the toxicity of the beta-amyloid peptide in a Drosophila model of Alzheimer's disease.
abstract: The mechanism by which aggregates of the beta-amyloid peptide (Abeta) mediate their toxicity is uncertain. We show here that the expression of the 42-amino-acid isoform of Abeta (Abeta(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) Abeta(1-42). Likewise, treatment with the iron-binding compound clioquinol increased the lifespan of flies expressing Arctic Abeta(1-42). The effect of iron appears to be mediated by oxidative stress as ferritin heavy chain co-expression reduced carbonyl levels in Abeta(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 Abeta(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 Abeta(1-42) toxicity in vivo and provide strong support for Alzheimer's disease therapies based on metal chelation.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge, UK. rival@ibdm.univ-mrs.fr
authors.forename: Thomas
authors.initials: T
authors.lastname: Rival
authors.forename: Richard M
authors.initials: RM
authors.lastname: Page
authors.forename: Dhianjali S
authors.initials: DS
authors.lastname: Chandraratna
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sendall
authors.forename: Edward
authors.initials: E
authors.lastname: Ryder
authors.forename: Beinan
authors.initials: B
authors.lastname: Liu
authors.forename: Huw
authors.initials: H
authors.lastname: Lewis
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosahl
authors.forename: Robert
authors.initials: R
authors.lastname: Hider
authors.forename: L M
authors.initials: LM
authors.lastname: Camargo
authors.forename: Mark S
authors.initials: MS
authors.lastname: Shearman
authors.forename: Damian C
authors.initials: DC
authors.lastname: Crowther
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D001052:Apoferritins / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D007464:Clioquinol / Q000494:pharmacology; D004195:Disease Models, Animal; D004330:Drosophila; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D009043:Motor Activity / Q000502:physiology; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D016229:Amyloid beta-Peptides; D007502:Iron Chelating Agents; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D007464:Clioquinol; D001052:Apoferritins; D007501:Iron; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1