Xudong Huang, Math P. Cuajungco, Craig S. Atwood, Mariana A. Hartshorn, Joel D. A.
Tyndall, Graeme R. Hanson, Karen C. Stokes, Michael Leopold, Gerd Multhaup, Lee E.
Goldstein, Richard C. Scarpa, Aleister J. Saunders, James Lim, Robert D. Moir, Charles Glabe,
Edmond F. Bowden, Colin L. Masters, David P. Fairlie, Rudolph E. Tanzi, and Ashley I. Bush.
Cu(II) Potentiation of Alzheimer A Neurotoxicity. Correlation with Cell-Free Hydrogen Peroxide Production and Metal Reduction, J. Biol. Chem. 274 :37111-37116, 1999.
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
H2O2 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 H2O2 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.
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