Electrochemical and conformational consequences of copper (Cu(I) and Cu(II)) binding to beta-amyloid(1-40)

Chembiochem. 2009 Apr 17;10(6):1045-55. doi: 10.1002/cbic.200800732.

Abstract

Copper-induced structural rearrangements of Abeta40 structure and its redox properties are described in this study. Electrochemical and fluorescent methods are used to characterise the behaviour of Abeta-Cu species. The data suggest that time-dependent folding of Abeta-Cu species may cause changes in the redox potentials.Extracellular deposits of beta-amyloid (Abeta) 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 Abeta(1-40) can bind copper with high affinity, but electrochemical properties of Abeta(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 Abeta(1-40) reduces the metal electrochemical activity. Formation of copper-Abeta(1-40) complexes is associated with alteration of the redox potential. The data reveal significant redox activity of fresh Abeta-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 Abeta-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 beta-sheet content as for the metal-free peptide. Although the redox activity of Abeta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / pharmacology
  • Cell Membrane / drug effects
  • Copper / chemistry
  • Copper / metabolism*
  • Copper / pharmacology*
  • Electrochemistry
  • Erythrocytes / drug effects
  • Erythrocytes / pathology
  • Fluorescent Dyes / metabolism
  • Hemolysis / drug effects
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Oxidation-Reduction
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism*
  • Peptide Fragments / pharmacology
  • Protein Structure, Secondary
  • Solubility
  • Time Factors

Substances

  • Amyloid beta-Peptides
  • Fluorescent Dyes
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • Copper