Substitution of isoleucine-31 by helical-breaking proline abolishes oxidative stress and neurotoxic properties of Alzheimer's amyloid beta-peptide.
Alzheimer's disease (AD) brain is characterized by excess deposition of the 42-amino acid amyloid beta-peptide [A(beta)(1-42)]. AD brain is under intense oxidative stress, and we have previously suggested that A(beta)(1-42) was associated with this increased oxidative stress. In addition, we previously demonstrated that the single methionine residue of A(beta)(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 A(beta)(1-42) is helical in aqueous micellar solutions, including that part of the protein containing Met35. Importantly, Cu(II)-binding induces alpha-helicity in A(beta) 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 A(beta)(1-42). Accordingly, we investigated A(beta)(1-42) in which the Ile31 residue was replaced with the helix-breaking amino acid, proline. The alpha-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 A(beta)(1-42)I31P were completely altered compared to native A(beta)(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.
Kanski
Jaroslaw
J
Department of Chemistry, University of Kentucky, Lexington, KY 40506-0055, USA.
Aksenova
Marina
M
Schöneich
Christian
C
Butterfield
D Allan
DA
D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity; D000818:Animals; D052160:Benzothiazoles; D002942:Circular Dichroism; D003300:Copper / Q000378:metabolism; D007532:Isoleucine / Q000737:chemistry*; D008854:Microscopy, Electron; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity; D011392:Proline / Q000737:chemistry*; D051381:Rats; D013844:Thiazoles / Q000378:metabolism
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D007532:Isoleucine; C009462:thioflavin T; D003300:Copper; D011392:Proline