Metalloenzyme-like activity of Alzheimer's disease beta-amyloid - Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2

Opazo C.; Huang, XD; Cherny, RA; Moir, RD; Roher, AE; White, AR; Cappai, R; Masters, CL; Tanzi, RE; Inestrosa, NC; Bush, AI

Abstract

?-Amyloid (A?) 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. A?·Cu complexes generate neurotoxic H2O2 from O2 through Cu2+ reduction, but the reaction mechanism has been unclear. We now report that A?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 ?M). The activity was inhibited by anti-A? antibodies, Cu2+ chelators, and Zn2+. Toxicity of A? in neuronal culture was consistent with catalytic H2O2 production. A? was not toxic in cell cultures in the absence of Cu2+, and dopamine (5 ?M) markedly exaggerated the neurotoxicity of 200 nM A?1-42·Cu. Therefore, microregional catalytic H2O2 production, combined with the exhaustion of reducing agents, may mediate the neurotoxicity of A? in Alzheimer's disease, and inhibitors of this novel activity may be of therapeutic value.

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Título según WOS: Metalloenzyme-like activity of Alzheimer's disease beta-amyloid - Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2
Título según SCOPUS: Metalloenzyme-like activity of Alzheimer's disease ?-amyloid: Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2
Título de la Revista: JOURNAL OF BIOLOGICAL CHEMISTRY
Volumen: 277
Número: 43
Editorial: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Fecha de publicación: 2002
Página de inicio: 40302
Página final: 40308
Idioma: English
URL: http://www.jbc.org/cgi/doi/10.1074/jbc.M206428200
DOI:

10.1074/jbc.M206428200

Notas: ISI, SCOPUS