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

Eur J Neurosci. 2009 Apr;29(7):1335-47. doi: 10.1111/j.1460-9568.2009.06701.x. Epub 2009 Mar 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Animals, Genetically Modified
  • Apoferritins / metabolism
  • Brain / drug effects
  • Brain / physiopathology
  • Clioquinol / pharmacology
  • Disease Models, Animal
  • Drosophila
  • Iron / metabolism*
  • Iron Chelating Agents / pharmacology
  • Kaplan-Meier Estimate
  • Motor Activity / physiology
  • Mutation
  • Neurons / drug effects
  • Neurons / physiology
  • Oligonucleotide Array Sequence Analysis
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics*
  • Peptide Fragments / genetics
  • Peptide Fragments / toxicity*
  • Reactive Oxygen Species / metabolism
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1


  • Amyloid beta-Peptides
  • Iron Chelating Agents
  • Peptide Fragments
  • Reactive Oxygen Species
  • amyloid beta-protein (1-42)
  • Clioquinol
  • Apoferritins
  • Iron
  • Superoxide Dismutase
  • Superoxide Dismutase-1