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Methionine oxidation: Implications for the mechanism of toxicity of the β-amyloid peptide from Alzheimer's disease

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Abstract

The amyloid β-peptide, Aβ is toxic to neurons and this toxicity plays a central role in the progression of Alzheimer's disease. The mechanism(s) by which Aβ exerts its toxicity has been hotly debated with several theories postulated. Here we discuss the role of oxidation of the sulfur atom of Met35 in Aβ42 (Met(O)Aβ), a modification that has significant implications for the mechanism of Aβ toxicity. Both Met(O)Aβ and its native form display toxicity to primary neuronal cells in culture which can be rescued by catalase, a H2O2 inhibitor and clioquinol a mild copper chelator. However both native Aβ and Met(O)Aβ differ substantially in primary and secondary structures, solubility, ability to penetrate lipid membranes, and oligomerization profiles. It is clearly evident that metals play an important role in the oxidation of Aβ to Met(O)Aβ via Fenton chemistry and that regulation of this pathway has a potential therapeutic application for the regulation of Alzheimer's disease.

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Authors and Affiliations

  1. Department of Pathology, The University of Melbourne, The Mental Health Research Institute of Victoria, Victoria, Parkville, Victoria, 3010, 3052, Australia

    Giuseppe D. Ciccotosto, Kevin J. Barnham, Robert A. Cherny, Colin L. Masters, Ashley I. Bush, Cyril C. Curtain, Roberto Cappai & Deborah Tew

  2. Laboratory for Oxidation Biology, Genetics and Aging Unit and Department of Psychiatry, Laborator, Harvard Medical School, Massachusetts General Hospital East, Charlestown, MA, USA

    Ashley I. Bush

  3. School of Physics and Materials Engineering, Monash University, Victoria, Australia

    Cyril C. Curtain

Authors
  1. Giuseppe D. Ciccotosto
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  2. Kevin J. Barnham
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  3. Robert A. Cherny
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  4. Colin L. Masters
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Ciccotosto, G.D., Barnham, K.J., Cherny, R.A. et al. Methionine oxidation: Implications for the mechanism of toxicity of the β-amyloid peptide from Alzheimer's disease. Int J Pept Res Ther 10, 413–417 (2003). https://doi.org/10.1007/s10989-004-2394-7

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  • DOI: https://doi.org/10.1007/s10989-004-2394-7

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