Oxidation of methionine 35 reduces toxicity of the amyloid beta-peptide(1–42) in neuroblastoma cells (IMR-32) via enzyme methionine sulfoxide reductase A expression and function

Abstract

The beta amyloid peptide (Aβ), the major protein component of brain senile plaques in Alzheimer's disease, is known to be directly responsible for the production of free radicals that may lead to neurodegeneration. Our recent evidence suggest that the redox state of methionine residue in position 35 (Met-35) of Aβ has the ability to deeply modify peptide's neurotoxic actions. Reversible oxidation of methionine in proteins involving the enzyme methionine sulfoxide reductase type A (MsrA) is postulated to serve a general antioxidant role and a decrease in MsrA has been implicated in Alzheimer's disease. In rat neuroblastoma cells (IMR-32), we used Aβ(1–42), in which the Met-35 is present in the reduced state, with a modified peptide with oxidized Met-35 (Aβ(1–42)Met35 OX), as well as an Aβ-derivative in which Met-35 is substituted with norleucine (Aβ(1–42)Nle35) to investigate the relationship between Met-35 redox state, expression and function of MsrA and reactive oxygen species (ROS) generation. The obtained results shown that MsrA activity, as well as mRNA levels, increase in IMR-32 cells treated with Aβ(1–42)Met35 OX, differently to that shown by the reduced derivative. The increase in MsrA function and expression was associated with a decline of ROS levels. None of these effects were observed when cells were exposed to Aβ containing oxidized Met35 (Aβ1–42)Met35 OX. Taken together, the results of the present study indicate that the differential toxicity of Aβ peptides containing reduced or oxidised Met-35 depends on the ability of the latter form to reduce ROS generation by enhancing MsrA gene expression and function and suggests the therapeutic potential of MsrA in Alzheimer's disease.