Role of methionine sulfoxide reductase in Alzheimer's disease

Abstract

Cellular oxidative damage has been implicated as one of the factors in Alzheimer's disease (AD) pathogenesis. One of the enzyme systems preventing protein oxidation in mammalian cells is the methionine sulfoxide reductase (MSR) system; MSR system is comprised of MSRA and MSRB, which reduce oxidized methionine residues (Met(O)) present in proteins back to methionine. Further, the MSR system scavenges reactive oxygen species (ROS), by permitting methionine residues in proteins to function as catalytic antioxidants. There is growing evidence from many studies on the affect of altered MSRA levels on AD progression in different animal models and, also that oxidized Met 35 will promote aggregation of toxic forms of Aß. Our research aims to further understand the role of MSRA and Met35 in the pathogenic processes of AD. For our studies we have used, AD transgenic mice, J20 APP-Tg that overexpresses Aß to analyze MSR levels and, variants of commercially available Aß (1-42) to assess the effect of methionine oxidation. Our preliminary results indicate that the level of MSRA was decreased in the transgenic mice as compared to the wild type mice. We have also observed in Aß peptide aggregation experiments, oxidized Met35 Aβformed high molecular weight fibrillar aggregates compared to the WT- Aβ and, if Met is replaced with norleucine (Nle) only monomers were formed. These results suggest that MSRA plays a role in Aß aggregation and these studies provide a potential therapeutic target for AD.