Alpha-2-Macroglobulin (alpha 2M) is the largest major nonimmunoglobulin protein in plasma. A common variant (29.5%) of caM leads to increased risk of Alzheimer's disease. Electrochemical methods were advanced for the detection of changes in protein structures based on the anodic response of tyrosine or tryptophan and histidine using different solid electrodes. A direct electrochemical method employing the alpha 2M adsorbed on glassy carbon (GC), boron doped diamond (BDD), edge-plane pyrolytic graphite (EPPG), and a gold electrode has been studied over the pH range 4.2-8.0 by differential pulse voltammetry (DPV). The alpha 2M oxidation mechanism occurs in two consecutive steps on boron doped diamond electrode, which is pH dependent, corresponding to the oxidation of tyrosine or tryptophan and histidine amino acid residues. For alpha 2M denaturation studies, the glassy carbon electrode was chosen due to the fact that the largest differences were observed in peak currents of native and denatured alpha 2M. The alpha 2M and urea concentrations were optimized by adsorptive stripping square wave voltammetry (SWAdSV) for denaturation in the solution phase. The developed adsorptive stripping method with GCE showed sensitive detection for native and denatured alpha 2M. The limit of detection was found as 9.85 mu g mL(-1) and 1.69 mu g mL(-1) for native and denatured alpha 2M, respectively. The possible oxidation mechanism of alpha 2M is also discussed in detail. (c) 2014 Elsevier B.V. All rights reserved.