Substitution of isoleucine-31 by helical-breaking proline abolishes oxidative stress and neurotoxic properties of Alzheimer's amyloid β-peptide (1-42)

Jaroslaw Kanski, Marina Aksenova, Christian Schöneich, D. Allan Butterfield

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95 Scopus citations

Abstract

Alzheimer's disease (AD) brain is characterized by excess deposition of the 42-amino acid amyloid β-peptide [Aβ(1-42)]. AD brain is under intense oxidative stress, and we have previously suggested that Aβ(1-42) was associated with this increased oxidative stress. In addition, we previously demonstrated that the single methionine residue of Aβ(1-42), residue 35, was critical for the oxidative stress and neurotoxic properties of this peptide. Others have shown that the C-terminal region of Aβ(1-42) is helical in aqueous micellar solutions, including that part of the protein containing Met35. Importantly, Cu(II)-binding induces α-helicity in Aβ in aqueous solution. Invoking the i + 4 rule of helices, we hypothesized that the carbonyl oxygen of Ile31 would interact with the S atom of Met35 to change the electronic environment of the sulfur such that molecular oxygen could lead to the production of a sulfuramyl free radical on Met35. If this hypothesis is correct, a prediction would be that breaking the helical interaction of Ile31 and Met35 would abrogate the oxidative stress and neurotoxic properties of Aβ(1-42). Accordingly, we investigated Aβ(1-42) in which the Ile31 residue was replaced with the helix-breaking amino acid, proline. The α-helical environment around Met35 was completely abolished as indicated by circular dichroism (CD)-spectroscopy. As a consequence, the aggregation, oxidative stress, Cu(II) reduction, and neurotoxic properties of Aβ(1-42)I31P were completely altered compared to native Aβ(1-42). The results presented here are consistent with the notion that interaction of Ile31 with Met35 may play an important role in the oxidative processes of Met35 contributing to the toxicity of the peptide.

Original languageEnglish
Pages (from-to)1205-1211
Number of pages7
JournalFree Radical Biology and Medicine
Volume32
Issue number11
DOIs
StatePublished - Jun 1 2002

Bibliographical note

Funding Information:
The authors thank Professor Paul Bummer of the UK College of Pharmacy for assistance with the CD-spectroscopy experiments. This work was supported in part by National Institutes of Health grants (AG-05119; AG-10836; AG-12423 to D.A.B.) and PO1AG12993 (to C.S.).

Keywords

  • Amyloid β-peptide
  • Free radicals
  • Methionine
  • Neurotoxicity
  • Protein oxidation

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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