Cu(II) potentiation of Alzheimer A beta neurotoxicity - Correlation with cell-free hydrogen peroxide production and metal reduction

Oxidative stress markers as well as high concentrations of copper are found in the vicinity of A beta amyloid deposits in Alzheimer's disease. The neu rotoxicity of A beta in cell culture has been linked to H2O2 generation by an unknown mechanism. We now report that Cu(II) markedly potentiates the ne urotoxicity exhibited by A beta in cell culture. The potentiation of toxici ty is greatest for A beta 1-42 > A beta 1-40 >> mouse/rat A beta 1-40, corr esponding to their relative capacities to reduce Cu(II) to Cu(I), form H2O2 in cell-free assays and to exhibit amyloid pathology. The copper complex o f A beta 1-42 has a highly positive formal reduction potential (approximate to+500-550 mV versus Ag/AgCl) characteristic of strongly reducing cupro-pr oteins. These findings suggest that certain redox active metal ions may be important in exacerbating and perhaps facilitating A beta-mediated oxidativ e damage in Alzheimer's disease.