Oxidative stress precedes fibrillar deposition of Alzheimer's disease amyloid beta-peptide (1-42) in a transgenic Caenorhabditis elegans model.
Alzheimer's disease is a progressive, neurodegenerative disorder characterized by senile plaques and neurofibrillary components. Abeta(1-42) is a principal component of senile plaques and is thought to be central to the pathogenesis of the disease. The Alzheimer's disease brain is under significant oxidative stress, and the Abeta(1-42) peptide is known to cause oxidative stress in vitro. One controversy in the amyloid hypothesis is whether or not Abeta plaques are required for toxicity. We have employed a temperature-inducible Abeta expression system in Caenorhabditis elegans to create a strain of worms, CL4176, in which Abeta(1-42) is expressed with a non-permissive temperature of 23 degrees C. The CL4176 strain allows examination of the temporal relationship between Abeta expression, oxidative stress, and Abeta fibril formation. CL4176 were under increased oxidative stress, evidenced by increased protein oxidation indexed by increased carbonyl levels, 24 and 32 h after temperature upshift as compared to the control strain, CL1175. The increased oxidative stress in CL4176 occurred in the absence of Abeta fibril formation, consistent with the notion that the toxic species in Abeta toxicity is pre-fibrillar Abeta and not the Abeta fibril. These results are discussed with reference to Alzheimer's disease.
Drake
Jennifer
J
Department of Chemistry and Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA.
Link
Christopher D
CD
Butterfield
D Allan
DA
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics; D017173:Caenorhabditis elegans / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression / Q000235:genetics; D009454:Neurofibrils / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity; D058225:Plaque, Amyloid / Q000378:metabolism*; D011497:Protein O-Methyltransferase / Q000032:analysis
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D011497:Protein O-Methyltransferase