Original Contribution SUBSTITUTION OF ISOLEUCINE-31 BY HELICAL-BREAKING PROLINE ABOLISHES OXIDATIVE STRESS AND NEUROTOXIC PROPERTIES OF

Abstract—Alzheimer’s disease (AD) brain is characterized by excess deposition of the 42-amino acid amyloid �-peptide [A�(1–42)]. AD brain is under intense oxidative stress, and we have previously suggested that A�(1–42) was associated with this increased oxidative stress. In addition, we previously demonstrated that the single methionine residue of A�(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�(1–42) is helical in aqueous micellar solutions, including that part of the protein containing Met35. Importantly, Cu(II)-binding induces �-helicity in A � 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�(1–42). Accordingly, we investigated A�(1–42) in which the Ile31 residue was replaced with the helix-breaking amino acid, proline. The �-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�(1–42)I31P were completely altered compared to native A�(1–42). The results presented here are consistent with the notion tha

Derivatives of Xanthic Acid are Novel Antioxidants: Application to Synaptosomes

Xanthic acids have long been known to act as reducing agents. Recently, D609, a tricyclodecanol derivative of xanthic acid, has been reported to have anti-apoptotic and anti-inflammatory properties that are attributed to specific inhibition of phosphatidyl choline phospholipase C (PC-PLC). However, because oxidative stress is involved in both of these cellular responses, the possibility that xanthates may act as antioxidants was investigated in the current study. Finding that xanthates efficiently scavenge hydroxyl radicals, the mechanism by which D609 and other xanthate derivatives may protect against oxidative damage was further examined. The xanthates studied, especially D609, mimic glutathione (GSH). Xanthates scavenge hydroxyl radicals and hydrogen peroxide, form disulfide bonds (dixanthogens), and react with electrophili