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 language | English |
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Pages (from-to) | 665-673 |
Number of pages | 9 |
Journal | Peptides |
Volume | 26 |
Issue number | 4 |
DOIs | |
State | Published - 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