Journal of Biological Chemistry
Volume 274, Issue 52, 24 December 1999, Pages 37111-37116
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PROTEIN CHEMISTRY AND STRUCTURE
Cu(II) Potentiation of Alzheimer Aβ Neurotoxicity: CORRELATION WITH CELL-FREE HYDROGEN PEROXIDE PRODUCTION AND METAL REDUCTION*

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Oxidative stress markers as well as high concentrations of copper are found in the vicinity of Aβ amyloid deposits in Alzheimer's disease. The neurotoxicity of Aβ in cell culture has been linked to H2O2generation by an unknown mechanism. We now report that Cu(II) markedly potentiates the neurotoxicity exhibited by Aβ in cell culture. The potentiation of toxicity is greatest for Aβ1–42 > Aβ1–40 ≫ mouse/rat Aβ1–40, 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 Aβ1–42 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 Aβ-mediated oxidative damage in Alzheimer's disease.

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*

This work was supported in part by grants from Prana Corp.; NIA, National Institutes of Health; Alliance for Aging Research (Paul Beeson Physician Faculty Scholar in Aging research award to A. I. B.); International Life Sciences Institute; the National Health and Medical Research Council of Australia; the Australian Research Council; and the Commonwealth of Massachusetts Research Center.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

FNb

Recipient of a National Research Service Award (NIA, National Institutes of Health).

FNh

Massachusetts General Hospital Medical Fund for Discovery fellow.