Metalloenzyme-like activity of Alzheimer's disease β-amyloid: Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2
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. "
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.Journal of Environmental Management 03/2015; 151:267-279. DOI:10.1016/j.jenvman.2014.11.024 · 3.19 Impact Factor
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- ". In addition, Cu + can donate two electrons to oxygen, generating H 2 O 2   , and further producing hydroxyl radicals (Fenton-type reaction)  . Iron accumulation is also present in cells associated with neuritic plaques in AD  , which results in the increase of oxidative stress. "
ABSTRACT: Oxidative stress plays a significant role in the pathogenesis of Alzheimer's disease (AD), a devastating disease of the elderly. The brain is more vulnerable than other organs to oxidative stress, and most of the components of neurons (lipids, proteins, and nucleic acids) can be oxidized in AD due to mitochondrial dysfunction, increased metal levels, inflammation, and β-amyloid (Aβ) peptides. Oxidative stress participates in the development of AD by promoting Aβ deposition, tau hyperphosphorylation, and the subsequent loss of synapses and neurons. The relationship between oxidative stress and AD suggests that oxidative stress is an essential part of the pathological process, and antioxidants may be useful for AD treatment.Neuroscience Bulletin 03/2014; 30(2). DOI:10.1007/s12264-013-1423-y · 1.83 Impact Factor
- "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). "
Dataset: Development of iron chelator