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Originally published In Press as doi:10.1074/jbc.M206428200 on August 20, 2002

J. Biol. Chem., Vol. 277, Issue 43, 40302-40308, October 25, 2002
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Metalloenzyme-like Activity of Alzheimer's Disease beta -Amyloid
Cu-DEPENDENT CATALYTIC CONVERSION OF DOPAMINE, CHOLESTEROL, AND BIOLOGICAL REDUCING AGENTS TO NEUROTOXIC H2O2*

Carlos OpazoDagger , Xudong Huang§, Robert A. Cherny, Robert D. Moir||, Alex E. Roher**, Anthony R. White, Roberto Cappai, Colin L. Masters, Rudolph E. Tanzi||, Nibaldo C. InestrosaDagger , and Ashley I. Bush§Dagger Dagger

From the Dagger  Centro de Regulación Celular y Patología, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 114-D, Chile, § Laboratory for Oxidation Biology, Genetics and Aging Research Unit, and Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129,  Oxidation Disorders Laboratory, Mental Health Research Institute of Victoria and Department of Pathology, the University of Melbourne, Parkville, Victoria 3052, Australia, || Genetics and Aging Research Unit and Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, and the ** Haldeman Laboratory for Alzheimer Disease Research, Sun Health Research Institute, Sun City, Arizona 85351

beta -Amyloid (Abeta ) 1-42, implicated in the pathogenesis of Alzheimer's disease, forms an oligomeric complex that binds copper at a CuZn superoxide dismutase-like binding site. Abeta ·Cu complexes generate neurotoxic H2O2 from O2 through Cu2+ reduction, but the reaction mechanism has been unclear. We now report that Abeta 1-42, when binding up to 2 eq of Cu2+, generates the H2O2 catalytically by recruiting biological reducing agents as substrates under conditions where the Cu2+ or reducing agents will not form H2O2 themselves. Cholesterol is an important substrate for this activity, as are vitamin C, L-DOPA, and dopamine (Vmax for dopamine = 34.5 nM/min, Km = 8.9 µM). The activity was inhibited by anti-Abeta antibodies, Cu2+ chelators, and Zn2+. Toxicity of Abeta in neuronal culture was consistent with catalytic H2O2 production. Abeta was not toxic in cell cultures in the absence of Cu2+, and dopamine (5 µM) markedly exaggerated the neurotoxicity of 200 nM Abeta 1-42·Cu. Therefore, microregional catalytic H2O2 production, combined with the exhaustion of reducing agents, may mediate the neurotoxicity of Abeta in Alzheimer's disease, and inhibitors of this novel activity may be of therapeutic value.

* This work was supported in part by National Health & Medical Research Council, National Institutes of Health Grants 2R01AG12685 (to A. I. B.) and 1K01MH02001 (to X. H.), Prana Biotechnology Ltd., and Grants Fondo de Investigación Avanzada en Áreas Prioritarias number 13980001, CIMM-ICA/006 (to N. C. I.) and Fondo Nacional de Desarrollo Científico y Tecnológico number 2990087, Dirección de Investigación y Postgrado (to C. O.).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.

Dagger Dagger To whom correspondence should be addressed: Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Massachusetts General Hospital, Bldg. 114, 16th St., Charlestown, MA 02129. Tel.: 617-726-8244; Fax: 617-724-1823; E-mail: bush@helix.mgh.harvard.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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