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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

ABSTRACT

β-Amyloid (Aβ) 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. Aβ·Cu complexes generate neurotoxic H2O2 from O2 through Cu2+ reduction, but the reaction mechanism has been unclear. We now report that Aβ1–42, when binding up to 2 eq of Cu2+, generates the H2O2catalytically 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 (V
maxfor dopamine = 34.5 nm/min, K
m = 8.9 μm). The activity was inhibited by anti-Aβ antibodies, Cu2+ chelators, and Zn2+. Toxicity of Aβ in neuronal culture was consistent with catalytic H2O2 production. Aβ was not toxic in cell cultures in the absence of Cu2+, and dopamine (5 μm) markedly exaggerated the neurotoxicity of 200 nm Aβ1–42·Cu. Therefore, microregional catalytic H2O2 production, combined with the exhaustion of reducing agents, may mediate the neurotoxicity of Aβ in Alzheimer's disease,
and inhibitors of this novel activity may be of therapeutic value.

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Available from: Xudong Huang, Jan 02, 2016
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    • "This abnormal redistribution of copper in AD may be a consequence of high affinity of Aβ, in particular Aβ42, to bind copper [23] [52] prior to Aβ deposition into amyloid plaques. When Aβ is in a complex with Cu 2+ ions, Cu 2+ reduction to Cu + in the presence of molecular oxygen can catalyze production of hydrogen peroxide, H 2 O 2 [55]. Hydrogen peroxide is a pro-oxidant molecule that is a substrate for the Fenton reaction, resulting in a highly reactive hydroxyl radical with the ability to modify carbonyl groups in proteins, and is one of the reactive oxygen species (ROS) linked to the oxidative stress hypothesis of AD [56]. "
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    ABSTRACT: Oligomeric assemblies are postulated to be proximate neurotoxic species in human diseases associated with aberrant protein aggregation. Their heterogeneous and transient nature makes their structural characterization difficult. Size distributions of oligomers of several amyloidogenic proteins, including amyloid β-protein (Aβ) relevant to Alzheimer's disease (AD), have been previously characterized in vitro by photo-induced cross-linking of unmodified proteins (PICUP) followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Due to non-physiological conditions associated with the PICUP chemistry, Aβ oligomers cross-linked by PICUP may not be representative of in vivo conditions. Here, we examine an alternative Copper and Hydrogen peroxide Induced Cross-linking of Unmodified Proteins (CHICUP), which utilizes naturally occurring divalent copper ions and hydrogen peroxide and does not require photo activation. Our results demonstrate that CHICUP and PICUP applied to the two predominant Aβ alloforms, Aβ40 and Aβ42, result in similar oligomer size distributions. Thioflavin T fluorescence data and atomic force microscopy images demonstrate that both CHICUP and PICUP stabilize Aβ oligomers and attenuate fibril formation. Relative to noncross-linked peptides, CHICUP-treated Aβ40 and Aβ42 cause prolonged disruption to biomimetic lipid vesicles. CHICUP-stabilized Aβ oligomers link the amyloid cascade, metal, and oxidative stress hypotheses of AD into a more comprehensive understanding of the molecular basis of AD pathology. Because copper and hydrogen peroxide are elevated in the AD brain, CHICUP-stabilized Aβ oligomers are biologically relevant and should be further explored as a new therapeutic target.
    Full-text · Article · Dec 2015 · Biochimica et Biophysica Acta
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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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    ABSTRACT: Globally, much weight is currently being placed on agriculture to provide food for the growing popu-lation as well as feedstock for the bioenergy industry. Unfortunately, the intensification of agricultural operations to satisfy these growing needs has been associated with a number of environmental and human health risks. A review of publications on the subject was conducted and emphasis was placed on articles focusing on agriculture, environment, and public health as well as their interactions. Supporting information was also gathered from publications of various agricultural and environmental agencies. Agricultural practices with potential negative implications on the environment and human health were identified broadly as: (a) utilization of biosolids and animal manures, (b) use of agricultural chemicals, (c) management of post-harvest residue, (d) irrigation, and (e) tillage operations. Soil, water, and air contamination by nutrients, heavy metals, pathogens, and pesticides, as well as air contamination by particulate matters, noxious gases, and pathogens were among the leading environmental impacts. Some of the human-health impacts identified included neurological and reproductive defects, cardiovascular risks, cancers and other diseases (of kidney, liver, lung, and skin), skin allergies, gastroenteritis, and methemoglobinemia. Continual awareness on the impacts of the reviewed agricultural practices on environmental quality and human health and the implementation of experimentally-backed best management practices in agricultural systems remain indispensable.
    Full-text · Article · Mar 2015 · Journal of Environmental Management
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    • "It should be noted here that the synapse is the site where A, Cu, Zn, and Fe ions are present in sufficiently high quantities to promote interaction. Bush et al. have investigated the reaction between amyloid protein and copper (II) ion, and have pointed out that oligomeric A (1-42) binds with copper(II) ions, and this A-Cu complexes generate neurotoxic H 2 O 2 from O 2 (Opaza et al. 2002), but the reaction mechanism of the H 2 O 2 formation in this process is not known. "

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