The elevated copper binding strength of amyloid-β aggregates allows the sequestration of copper from albumin: a pathway to accumulation of copper in senile plaques

Biochemistry. 2013 Jan 22;52(3):547-56. doi: 10.1021/bi301053h. Epub 2013 Jan 11.

Abstract

Copper coexists with amyloid-β (Aβ) peptides at a high concentration in the senile plaques of Alzheimer's disease (AD) patients and has been linked to oxidative damage associated with AD pathology. However, the origin of copper and the driving force behind its accumulation are unknown. We designed a sensitive fluorescent probe, Aβ(1-16)(Y10W), by substituting the tyrosine residue at position 10 in the hydrophilic domain of Aβ(1-42) with tryptophan. Upon mixing Cu(II), Aβ(1-16)(Y10W), and aliquots of Aβ(1-42) taken from samples incubated for different lengths of time, we found that the Cu(II) binding strength of aggregated Aβ(1-42) has been elevated by more than 2 orders of magnitude with respect to that of monomeric Aβ(1-42). Electron paramagnetic spectroscopic measurements revealed that the Aβ(1-42) aggregates, unlike their monomeric form, can seize copper from human serum albumin, an abundant copper-containing protein in brain and cerebrospinal fluid. The significantly elevated binding strength of the Aβ(1-42) aggregates can be rationalized by a Cu(II) coordination sphere constituted by three histidines from two adjacent Aβ(1-42) molecules. Our work demonstrates that the copper binding affinity of Aβ(1-42) is dependent on its aggregation state and provides new insight into how and why senile plaques accumulate copper in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Chromatography, Gel
  • Copper / analysis
  • Copper / chemistry
  • Copper / metabolism*
  • Electron Spin Resonance Spectroscopy
  • Histidine / chemistry
  • Histidine / metabolism
  • Humans
  • Kinetics
  • Microscopy, Atomic Force
  • Models, Molecular
  • Molecular Weight
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Plaque, Amyloid / chemistry
  • Plaque, Amyloid / metabolism*
  • Protein Denaturation
  • Serum Albumin / metabolism*
  • Serum Albumin, Human
  • Spectrometry, Fluorescence
  • Tryptophan / chemistry
  • Tryptophan / metabolism

Substances

  • ALB protein, human
  • Amyloid beta-Peptides
  • Mutant Proteins
  • Peptide Fragments
  • Serum Albumin
  • amyloid beta-protein (1-16)
  • amyloid beta-protein (1-42)
  • Histidine
  • Copper
  • Tryptophan
  • Serum Albumin, Human