Oxidative stress precedes fibrillar deposition of Alzheimer’s disease amyloid -peptide (1–42) in a transgenic Caenorhabditis elegans model

Alzheimer’s disease is a progressive, neurodegenerative disorder characterized by senile plaques and neurofibrillary components. A (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 A (1–42) peptide is known to cause oxidative stress in vitro. One controversy in the amyloid hypothesis is whether or not A plaques are required for toxicity. We have employed a temperature-inducible A expression system in Caenorhabditis elegans to create a strain of worms, CL4176, in which A (1–42) is expressed with a non-permissive temperature of 23 ◦C. The CL4176 strain allows examination of the temporal relationship between A expression, oxidative stress, and A 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 A fibril formation, consistent with the notion that the toxic species in A toxicity is pre-fibrillar A and not the A fibril. These results are discussed with reference to Alzheimer’s disease. © 2002 Elsevier Science Inc. All rights reserved.