A Functional Role for A in Metal Homeostasis? N-Truncation and High-Affinity Copper Binding

Accumulation of the -amyloid (A) peptide in extracellular senile plaques rich in copper and zinc is a defining pathological feature of Alzheimers disease (AD). The A1-x (x=16/28/40/42) peptides have been the primary focus of Cu-II binding studies for more than 15years; however, the N-truncated A4-42 peptide is a major A isoform detected in both healthy and diseased brains, and it contains a novel N-terminal FRH sequence. Proteins with His at the third position are known to bind Cu-II avidly, with conditional logK values at pH7.4 in the range of 11.0-14.6, which is much higher than that determined for A1-x peptides. By using A4-16 as a model, it was demonstrated that its FRH sequence stoichiometrically binds Cu-II with a conditional K-d value of 3x10(-14)M at pH7.4, and that both A4-16 and A4-42 possess negligible redox activity. Combined with the predominance of A4-42 in the brain, our results suggest a physiological role for this isoform in metal homeostasis within the central nervous system.