Neurotoxic, redox-competent Alzheimer's beta-amyloid is released from lipid membrane by methionine oxidation.
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.
Barnham
Kevin J
KJ
Department of Pathology, The University of Melbourne and The Mental Health Research Institute of Victoria, Victoria 3010, Australia. kbarnham@unimelb.edu.au
Ciccotosto
Giuseppe D
GD
Tickler
Anna K
AK
Ali
Feda E
FE
Smith
Danielle G
DG
Williamson
Nicholas A
NA
Lam
Yuen-Han
YH
Carrington
Darryl
D
Tew
Deborah
D
Kocak
Gulcan
G
Volitakis
Irene
I
Separovic
Frances
F
Barrow
Colin J
CJ
Wade
John D
JD
Masters
Colin L
CL
Cherny
Robert A
RA
Curtain
Cyril C
CC
Bush
Ashley I
AI
Cappai
Roberto
R
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
D016229:Amyloid beta-Peptides; D007477:Ions; D008051:Lipid Bilayers; D010455:Peptides; D003300:Copper; D008715:Methionine; D006861:Hydrogen Peroxide; D010100:Oxygen