Substoichiometric levels of Cu2+ ions accelerate the kinetics of fiber formation and promote cell toxicity of amyloid-{beta} from Alzheimer disease

J Biol Chem. 2010 Dec 31;285(53):41533-40. doi: 10.1074/jbc.M110.171355. Epub 2010 Oct 25.

Abstract

A role for Cu(2+) ions in Alzheimer disease is often disputed, as it is believed that Cu(2+) ions only promote nontoxic amorphous aggregates of amyloid-β (Aβ). In contrast with currently held opinion, we show that the presence of substoichiometric levels of Cu(2+) ions in fact doubles the rate of production of amyloid fibers, accelerating both the nucleation and elongation of fiber formation. We suggest that binding of Cu(2+) ions at a physiological pH causes Aβ to approach its isoelectric point, thus inducing self-association and fiber formation. We further show that Cu(2+) ions bound to Aβ are consistently more toxic to neuronal cells than Aβ in the absence of Cu(2+) ions, whereas Cu(2+) ions in the absence of Aβ are not cytotoxic. The degree of Cu-Aβ cytotoxicity correlates with the levels of Cu(2+) ions that accelerate fiber formation. We note the effect appears to be specific for Cu(2+) ions as Zn(2+) ions inhibit the formation of fibers. An active role for Cu(2+) ions in accelerating fiber formation and promoting cell death suggests impaired copper homeostasis may be a risk factor in Alzheimer disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / chemistry*
  • Animals
  • Biophysics / methods
  • Cell Survival
  • Copper / chemistry*
  • Hydrogen-Ion Concentration
  • Ions
  • Isoelectric Point
  • Kinetics
  • Microscopy, Electron, Transmission / methods
  • Neurons / metabolism
  • PC12 Cells
  • Protein Folding
  • Rats
  • Zinc / chemistry

Substances

  • Amyloid beta-Peptides
  • Ions
  • Copper
  • Zinc