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

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-? (A?). 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 A? to approach its isoelectric point, thus inducing self-association and fiber formation. We further show that Cu(2+) ions bound to A? are consistently more toxic to neuronal cells than A? in the absence of Cu(2+) ions, whereas Cu(2+) ions in the absence of A? are not cytotoxic. The degree of Cu-A? 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.

SUBMITTER: Sarell CJ 

PROVIDER: S-EPMC3009880 | biostudies-other | 2010 Dec

REPOSITORIES: biostudies-other