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Neurotoxic, redox-competent Alzheimer's --amyloid is released from lipid membrane by methionine oxidation

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posted on 2003-10-31, 00:00 authored by K Barnham, G Ciccotosto, A Tickler, F Ali, D Smith, N Williamson, Y H Lam, D Carrington, D Tew, G Kocak, I Volitakis, F Separovic, Colin BarrowColin Barrow, J Wade, C Masters, R Cherny, C Curtain, A Bush, R Cappai
The amyloid β 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 Aβ peptide with the sulfur atom of Met-35 oxidized to a sulfoxide (Met(O)Aβ) 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 Aβ. However, unlike the unoxidized peptide, Met(O)Aβ is unable to penetrate lipid membranes to form ion channel-like structures, and β-sheet formation is inhibited, phenomena that are central to some theories for Aβ toxicity. Our results show that, like the unoxidized peptide, Met(O)Aβ will coordinate Cu2+ and reduce the oxidation state of the metal and still produce H2O2. We hypothesize that Met(O)Aβ production contributes to the elevation of soluble Aβ seen in the brain in Alzheimer's disease.

History

Journal

Journal of biological chemistry

Volume

278

Issue

44

Pagination

42959 - 42965

Publisher

American Society for Biochemistry and Molecular Biology

Location

Bethesda, Md.

ISSN

0021-9258

eISSN

1083-351X

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

2003, American Society for Biochemistry and Molecular Biology

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