Copper binding to the amyloid-β (Aβ) peptide associated with Alzheimer's disease -: Folding, coordination geometry, pH dependence, stoichiometry, and affinity of Aβ-(1-28):: Insights from a range of complementary spectroscopic techniques

There is now direct evidence that copper is bound to amyloid-beta peptide (Abeta) in senile plaque of Alzheimer's disease. Copper is also linked with the neurotoxicity of Abeta and free radical damage, and Cu2+ chelators represent a possible therapy for Alzheimer's disease. We have therefore used a range of complementary spectroscopies to characterize the coordination of Cu2+ to Abeta in solution. The mode of copper binding is highly pH-dependent. EPR spectroscopy indicates that both coppers have axial, Type II coordination geometry, square-planar or square-pyramidal, with nitrogen and oxygen ligands. Circular dichroism studies indicate that copper chelation causes a structural transition of Abeta. Competition studies with glycine and L-histidine indicate that copper binds to Abeta- (1 -28) at pH 7.4 with an affinity of K-a similar to10(7) M-1. H-1 NMR indicates that histidine residues are involved in Cu2+ coordination but that Tyr(10) is not. Studies using analogues of Abeta- (1 - 28) in which each of the histidine residues have been replaced by alanine or in which the N terminus is acetylated suggest that the N terminus and His(13) are crucial for Cu2+ binding and that His(6) and His(14) are also implicated. Evidence for the link between Alzheimer's disease and Cu2+ is growing, and our studies have made a significant contribution to understanding the mode of Cu2+ binding to Abeta in solution.