title: Neurotoxic, redox-competent Alzheimer's beta-amyloid is released from lipid membrane by methionine oxidation.
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.
authors.affiliation: Department of Pathology, The University of Melbourne and The Mental Health Research Institute of Victoria, Victoria 3010, Australia. kbarnham@unimelb.edu.au
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Giuseppe D
authors.initials: GD
authors.lastname: Ciccotosto
authors.forename: Anna K
authors.initials: AK
authors.lastname: Tickler
authors.forename: Feda E
authors.initials: FE
authors.lastname: Ali
authors.forename: Danielle G
authors.initials: DG
authors.lastname: Smith
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Williamson
authors.forename: Yuen-Han
authors.initials: YH
authors.lastname: Lam
authors.forename: Darryl
authors.initials: D
authors.lastname: Carrington
authors.forename: Deborah
authors.initials: D
authors.lastname: Tew
authors.forename: Gulcan
authors.initials: G
authors.lastname: Kocak
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.forename: Frances
authors.initials: F
authors.lastname: Separovic
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Barrow
authors.forename: John D
authors.initials: JD
authors.lastname: Wade
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cherny
authors.forename: Cyril C
authors.initials: CC
authors.lastname: Curtain
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D003300:Copper / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000494:pharmacology; D007477:Ions; D008051:Lipid Bilayers / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008715:Methionine / Q000378:metabolism*; D051379:Mice; D008858:Microscopy, Phase-Contrast; D009474:Neurons / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D007477:Ions; D008051:Lipid Bilayers; D010455:Peptides; D003300:Copper; D008715:Methionine; D006861:Hydrogen Peroxide; D010100:Oxygen