Kinetics of the Interactions between Copper and Amyloid‐β with FAD Mutations and Phosphorylation at the N terminus

Mutations and post-translational modifications of amyloid- (A) peptide in its Nterminus have been shown to increase fibril formation, yet the molecular mechanism is not clear. Here we investigated the kinetics of the interactions of copper with two A peptides containing Familial Alzheimer's disease (FAD) mutations (English (H6R) and Tottori (D7N)), as well as with A peptide phosphorylated at serine8 (pS8). All three peptides bind to copper with a similar rate as the wild-type (wt). The dissociation rates follow the order pS8>H6R>wt>D7N; the interconversion between the two coordinating species occurs 50% faster for H6R and pS8, whereas D7N had only a negligible effect. Interestingly, the rate of ternary complex (copper-bridged heterodimer) formation for the modified peptides was significantly faster than that for wt, thus leading us to propose that FAD and sporadic AD might share a kinetic origin for the enhanced oligomerisation of A beta.