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

Accumulation of the β‐amyloid (Aβ) peptide in extracellular senile plaques rich in copper and zinc is a defining pathological feature of Alzheimer′s disease (AD). The Aβ1–x (x=16/28/40/42) peptides have been the primary focus of Cu^II binding studies for more than 15 years; however, the N‐truncated Aβ4–42 peptide is a major Aβ 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 log K values at pH 7.4 in the range of 11.0–14.6, which is much higher than that determined for Aβ1–x peptides. By using Aβ4–16 as a model, it was demonstrated that its FRH sequence stoichiometrically binds Cu^II with a conditional K_d value of 3×10⁻¹⁴ M at pH 7.4, and that both Aβ4–16 and Aβ4–42 possess negligible redox activity. Combined with the predominance of Aβ4–42 in the brain, our results suggest a physiological role for this isoform in metal homeostasis within the central nervous system.