Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease

A role for Cu2+ ions in Alzheimer disease is often disputed, as it is believed that Cu2+ ions only promote nontoxic amorphous aggregates of amyloid-beta (A beta). In contrast with currently held opinion, we show that the presence of substoichiometric levels of Cu2+ 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 Cu2+ ions at a physiological pH causes A beta to approach its isoelectric point, thus inducing self-association and fiber formation. We further show that Cu2+ ions bound to A beta are consistently more toxic to neuronal cells than A beta in the absence of Cu2+ ions, whereas Cu2+ ions in the absence of A beta are not cytotoxic. The degree of Cu-A beta cytotoxicity correlates with the levels of Cu2+ ions that accelerate fiber formation. We note the effect appears to be specific for Cu2+ ions as Zn2+ ions inhibit the formation of fibers. An active role for Cu2+ ions in accelerating fiber formation and promoting cell death suggests impaired copper homeostasis may be a risk factor in Alzheimer disease.