Fenton chemistry and oxidative stress mediate the toxicity of the beta-amyloid peptide in a Drosophila model of Alzheimer's disease.
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.
Rival
Thomas
T
Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge, UK. rival@ibdm.univ-mrs.fr
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Richard M
RM
Chandraratna
Dhianjali S
DS
Sendall
Timothy J
TJ
Ryder
Edward
E
Liu
Beinan
B
Lewis
Huw
H
Rosahl
Thomas
T
Hider
Robert
R
Camargo
L M
LM
Shearman
Mark S
MS
Crowther
Damian C
DC
Lomas
David A
DA
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
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