One- and Two-Electron Oxidations of ?-Amyloid 25-35 by Carbonate Radical Anion (CO 3o-) and Peroxymonocarbonate (HCO 4-): Role of Sulfur in Radical Reactions and Peptide Aggregation

The ?-amyloid (A?) peptide plays a key role in the pathogenesis of Alzheimer's disease. The methionine (Met) residue at position 35 in A? C-terminal domain is critical for neurotoxicity, aggregation, and free radical formation initiated by the peptide. The role of Met in modulating toxicological properties of A? most likely involves an oxidative event at the sulfur atom. We therefore investigated the one- or two-electron oxidation of the Met residue of A?25-35 fragment and the effect of such oxidation on the behavior of the peptide. Bicarbonate promotes two-electron oxidations mediated by hydrogen peroxide after generation of peroxymonocarbonate (HCO4-, PMC). The bicarbonate/carbon dioxide pair stimulates one-electron oxidations mediated by carbonate radical anion (CO3o-). PMC efficiently oxidizes thioether sulfur of the Met residue to sulfoxide. Interestingly, such oxidation hampers the tendency of A? to aggregate. Conversely, CO3o- causes the one-electron oxidation of methionine residue to sulfur radical cation (MetSo+). The formation of this transient reactive intermediate during A? oxidation may play an important role in the process underlying amyloid neurotoxicity and free radical generation.