Neurotoxic,redox-competent Alzheimer's beta-amyloid is released from lipid membrane by methionine oxidation |
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Authors: | Barnham Kevin J Ciccotosto Giuseppe D Tickler Anna K Ali Feda E Smith Danielle G Williamson Nicholas A Lam Yuen-Han Carrington Darryl Tew Deborah Kocak Gulcan Volitakis Irene Separovic Frances Barrow Colin J Wade John D Masters Colin L Cherny Robert A Curtain Cyril C Bush Ashley I Cappai Roberto |
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Institution: | Department of Pathology, The University of Melbourne and The Mental Health Research Institute of Victoria, Victoria 3010, Australia. kbarnham@unimelb.edu.au |
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Abstract: | The amyloid beta peptide is toxic to neurons, and it is believed that this toxicity plays a central role in the progression of Alzheimer's disease. The mechanism of this toxicity is contentious. Here we report that an Abeta peptide with the sulfur atom of Met-35 oxidized to a sulfoxide (Met(O)Abeta) is toxic to neuronal cells, and this toxicity is attenuated by the metal chelator clioquinol and completely rescued by catalase implicating the same toxicity mechanism as reduced Abeta. However, unlike the unoxidized peptide, Met(O)Abeta is unable to penetrate lipid membranes to form ion channel-like structures, and beta-sheet formation is inhibited, phenomena that are central to some theories for Abeta toxicity. Our results show that, like the unoxidized peptide, Met(O)Abeta will coordinate Cu2+ and reduce the oxidation state of the metal and still produce H2O2. We hypothesize that Met(O)Abeta production contributes to the elevation of soluble Abeta seen in the brain in Alzheimer's disease. |
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