Neurotoxicity and oxidative stress in D1M-substituted Alzheimer's Aβ(1-42): Relevance to N-terminal methionine chemistry in small model peptides

Debra Boyd-Kimball, Rukhsana Sultana, Hafiz Mohmmad-Abdul, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Small model peptides containing N-terminal methionine are reported to form sulfur-centered-free radicals that are stabilized by the terminal N atom. To test whether a similar chemistry would apply to a disease-relevant longer peptide, Alzheimer's disease (AD)-associated amyloid beta-peptide 1-42 was employed. Methionine at residue 35 of this 42-mer has been shown to be a key amino acid residue involved in amyloid beta-peptide 1-42 [Aβ1-42]-mediated toxicity and therefore, the pathogenesis of AD. Previous studies have shown that mutation of the methionine residue to norleucine abrogates the oxidative stress and neurotoxic properties of Aβ(1-42). In the current study, we examined if the position of methionine at residue 35 is a criterion for toxicity. In doing so, we tested the effects of moving methionine to the N-terminus of the peptide in a synthetic peptide, Aβ(1-42)D1M, in which methionine was substituted for aspartic acid at the N-terminus of the peptide and all subsequent residues from D1 to L34 were shifted one position towards the carboxy-terminus. Aβ(1-42)D1M exhibited oxidative stress and neurotoxicity properties similar to those of the native peptide, Aβ(1-42), all of which are inhibited by the free radical scavenger Vitamin E, suggesting that reactive oxygen species may play a role in the Aβ-mediated toxicity. Additionally, substitution of methionine at the N-terminus by norleucine, Aβ(1-42)D1Nle, completely abrograted the oxidative stress and neurotoxicity associated with the Aβ(1-42)D1M peptide. The results of this study validate the chemistry reported for short peptides with N-terminal methionines in a disease-relevant peptide.

Original languageEnglish
Pages (from-to)665-673
Number of pages9
JournalPeptides
Volume26
Issue number4
DOIs
StatePublished - Apr 2005

Bibliographical note

Funding Information:
This work was supported in part by NIH grants [AG-05119; AG-10836].

Keywords

  • Amyloid beta-peptide
  • Free radicals
  • Methionine
  • Neurotoxicity

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Endocrinology
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'Neurotoxicity and oxidative stress in D1M-substituted Alzheimer's Aβ(1-42): Relevance to N-terminal methionine chemistry in small model peptides'. Together they form a unique fingerprint.

Cite this