Cu(II) Potentiation of Alzheimer Aβ Neurotoxicity

Abstract

Oxidative stress markers as well as high concentrations of copper are found in the vicinity of A amyloid deposits in Alzheimer's disease. The neurotoxicity of A in cell culture has been linked to H 2 O 2 generation by an unknown mechanism. We now report that Cu(II) markedly potentiates the neurotoxicity exhibited by A in cell culture. The potentiation of toxicity is greatest for A1-42 > A1-40 > > mouse/rat A1-40, corresponding to their relative capacities to reduce Cu(II) to Cu(I), form H 2 O 2 in cell-free assays and to exhibit amyloid pathology. The copper complex of A1-42 has a highly positive formal reduction potential (500 -550 mV versus Ag/AgCl) characteristic of strongly reducing cuproproteins. These findings suggest that certain redox active metal ions may be important in exacerbating and perhaps facilitating A-mediated oxidative damage in Alzheimer's disease.