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

Angew Chem Int Ed Engl. 2015 Sep 1;54(36):10460-4. doi: 10.1002/anie.201502644. Epub 2015 Jul 14.


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 Kd 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.

Keywords: Alzheimer's disease; amyloid; bioinorganic chemistry; copper; peptides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / physiology*
  • Copper / metabolism*
  • Homeostasis*


  • Amyloid beta-Peptides
  • Copper