β-AMYLOID25-35 MODIFICATION BY OXIDANTS DERIVED FROM BICARBONATE/CARBON DIOXIDE PAIR

The β-amyloid plays a key role in the pathogenesis of Alzheimer’s disease and contains a methionine residue at position 35 in its C-terminal domain which is critical for neurotoxicity, aggregation and free radical formation initiated by the peptide. The role of methionine in the toxicological properties of β-amyloid most likely involves an oxidative event at the sulfur atom. Many recent studies have demonstrated that the biologically ubiquitous bicarbonate/carbon dioxide pair stimulates oxidation, peroxidation and nitration of several biological targets. Hence, it is appropriate and timely to recognize that the main physiological buffer is active in redox processes. At physiological level, the bicarbonate/carbon dioxide pair, stimulates one-electron oxidations mediated by peroxynitrite and SOD with the intermediacy of carbonate anion radical (CO3•−). Furthermore, bicarbonate promotes two-electron oxidations mediated by hydrogen peroxide after generation of peroxymonocarbonate (HCO4−). We therefore investigated the ability of peroxymonocarbonate and carbonate anion radical to oxidatively modify methionine residue of β-amyloid and the effect of such oxidations on the behaviour of the β-amyloid25‒35 fragment. Peroxymonocarbonate efficiently oxidizes thioether sulfur of methionine (Met) residue of β-amyloid to sulfoxide (MetSO). Interestingly, such oxidation counteracts the tendency of β-amyloid to aggregate. Conversely, carbonate anion radical causes the one-electron oxidation of methionine residue to its radical cation (MetS•+). The formation of this transient reactive intermediate during β-amyloid25‒35 fragment oxidation may play an important role in the process underlying β-amyloid neurotoxicity and free radical generation