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

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

ABSTRACT 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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    • ". 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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    • "Chelators provide a " three-pronged " mode of action. First, since iron and copper are suggested to play an important role in the self-assembly and neurotoxicity of Ab (Atwood et al., 2004; Bush et al., 1994; Exley, 2006; Hayashi et al., 2007; Jobling et al., 2001; Nakamura et al., 2007), Ab toxicity is expectedly attenuated by such chelators (Huang et al., 1999; Opazo et al., 2002; Rottkamp et al., 2001; Schubert & Chevion, 1995). In fact, the ability of Ab to sequestrate redox metals likely explains conflicting in vivo and in vitro reports demonstrating Ab as both oxidant (Behl, Davis, Cole, & Schubert, 1992) and antioxidant (Hayashi et al., 2007; Nakamura et al., 2007; Nunomura et al., 2001; Smith, Casadesus, Joseph, & Perry, 2002). "
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