Neurotoxicity and oxidative stress in D1M-substituted Alzheimer's A beta(1-42): relevance to N-terminal methionine chemistry in small model peptides.
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 [A beta1-42]-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 A beta(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, A beta(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. A beta(1-42)D1M exhibited oxidative stress and neurotoxicity properties similar to those of the native peptide, A beta(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 A beta-mediated toxicity. Additionally, substitution of methionine at the N-terminus by norleucine, A beta(1-42)D1Nle, completely abrogated the oxidative stress and neurotoxicity associated with the A beta(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.
Boyd-Kimball
Debra
D
Department of Chemistry, Center for Membrane Sciences, University of Kentucky, Lexington, KY 40506-0055, USA.
Sultana
Rukhsana
R
Mohmmad-Abdul
Hafiz
H
Butterfield
D Allan
DA
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000633:toxicity / Q000648:ultrastructure; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism; D008715:Methionine / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology* / Q000633:toxicity / Q000648:ultrastructure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42); D003300:Copper; D008715:Methionine