Substoichiometric levels of Cu2+ ions accelerate the kinetics of fiber formation and promote cell toxicity of amyloid-{beta} from Alzheimer disease.
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.
Sarell
Claire J
CJ
School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom.
Wilkinson
Shane R
SR
Viles
John H
JH
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001703:Biophysics / Q000379:methods; D002470:Cell Survival; D003300:Copper / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007477:Ions; D007526:Isoelectric Point; D007700:Kinetics; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D017510:Protein Folding; D051381:Rats; D015032:Zinc / Q000737:chemistry
D016229:Amyloid beta-Peptides; D007477:Ions; D003300:Copper; D015032:Zinc