Opazo, C. et al. Metalloenzyme-like activity of Alzheimer's disease -amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2. J. Biol. Chem. 277, 40302-40308

Centro de Regulación Celular y Patologia, Departamento de Biologia Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 114-D, Chile.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2002; 277(43):40302-8. DOI: 10.1074/jbc.M206428200
Source: PubMed


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 H(2)O(2) from O(2) through Cu(2+) reduction, but the reaction mechanism has been unclear. We now report that Abeta1-42, when binding up to 2 eq of Cu(2+), generates the H(2)O(2) catalytically by recruiting biological reducing agents as substrates under conditions where the Cu(2+) or reducing agents will not form H(2)O(2) themselves. Cholesterol is an important substrate for this activity, as are vitamin C, L-DOPA, and dopamine (V(max) for dopamine = 34.5 nm/min, K(m) = 8.9 microm). The activity was inhibited by anti-Abeta antibodies, Cu(2+) chelators, and Zn(2+). Toxicity of Abeta in neuronal culture was consistent with catalytic H(2)O(2) production. Abeta was not toxic in cell cultures in the absence of Cu(2+), and dopamine (5 microm) markedly exaggerated the neurotoxicity of 200 nm Abeta1-42.Cu. Therefore, microregional catalytic H(2)O(2) 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.

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    • "Chronic Cu toxicity has also been linked to neurological defects and liver disease (Uriu-Adams and Keen, 2005). Copper toxicity has also been linked to a number of human diseases such as Wilson's disease (Müller et al., 2004) and to Alzheimer's disease (Miranda et al., 2000; Opazo et al., 2002). Lead entry into the human body system could occur through ingestion and/or inhalation. "
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    • "It has been well established that Aβ plaques are rich in metal ions (Opazo et al., 2002). These relatively high concentrations of metals within the plaques compared to adjacent tissue have been reaffirmed using a variety of bioimaging techniques. "
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    • ". In addition, Cu + can donate two electrons to oxygen, generating H 2 O 2 [72] [73] , and further producing hydroxyl radicals (Fenton-type reaction) [74] . Iron accumulation is also present in cells associated with neuritic plaques in AD [75] , which results in the increase of oxidative stress. "
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