Electrochemical and Conformational Consequences of Copper (CuI and CuII) Binding to β-Amyloid(1-40)

Extracellular deposits of beta-amyloid (A beta) into senile plaques are the major features observed in brains of Alzheimer's disease (AD) patients. A high concentration of copper has been associated with insoluble amyloid plaques. It is known that A beta(1-40) can bind copper with high affinity, but electrochemical properties of A beta(1-40)-Cu complexes are not well-characterised. In this study we demonstrate that complexation of copper (both as Cu-I and Cu-II) by A beta(1-40) reduces the metal electrochemical activity. Formation of copper-A beta(1-40) complexes is associated with alteration of the redox potential. The data reveal significant redox activity of fresh A beta-copper solutions. However, copper-induced structural rearrangements of the peptide, documented by CD, correspond with time-dependent changes of formal reduction potentials (E-0') of the complex. Fluorescent and electrochemical (cyclic voltammetry and differential pulse voltammetry) techniques suggest that reduction of the redox activity by A beta-Cu complexes could be attributed to conformational changes that diminished copper accessibility to the external environment. According to our evidence, conformational rearrangements, induced by copper binding to amyloid, elongate the time necessary to attain the same P-sheet content as for the metal-free peptide. Although the redox activity of A beta-Cu complexes diminishes in a time-dependent manner, they are not completely devoid of toxicity as they destabilize red blood cells osmotic fragility, even after prolonged incubation.