Metalloenzyme-like activity of Alzheimer's disease beta-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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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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ABSTRACT: A new series of oxamide (2a–s) and fumaramide derivatives (3a–s) was synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors against Alzheimer’s disease (AD). Their inhibitory ability was compared to chosen reference compounds (galantamine bromide, neostigmine bromide, and ambenonium dichloride). Lineweaver–Burk plot and molecular docking studies showed that one of the most potent compounds 3o (IC50 = 0.03 µM) could bind to both catalytic and peripheral active sites of AChE and it exhibited mixed-type inhibition. Moreover, it showed excellent metal chelating properties. The ethylene bridge, as the linker between the two carbonyl groups of the fumaramide derivatives, seemed to allow the fumaramide derivatives to be more effective than the oxamide derivatives on AChE inhibition. A similar situation was seen on BuChE inhibition, except for 2a and 2h. These results imply that the presence of an ethylene bridge in the inhibitors had more influence on the inhibition of AChE and BuChE.Medicinal Chemistry Research 02/2015; 24(2). DOI:10.1007/s00044-014-1152-4 · 1.61 Impact Factor
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ABSTRACT: Copper ions are indispensible to life and maintaining tight control over the homeostasis of copper ions in the body is a prerequisite to sustaining health. Aberrations in normal copper levels, both systemic as well as on a tissue or cellular scale are implicated in a wide range of diseases, such as Menkes disease, Wilson's disease, Alzheimer's disease, Parkinson's disease and transmissible spongiform encephalopathy (prion diseases). The current understanding of how copper influences these diseases is described. The field of fluorescent copper sensors, both functioning via a reaction based mechanism as well as by directly binding copper ions has known an inflation in recent years, and the importance of this field to elucidating the role of copper in cell biology is pointed out. Progress in these tightly interwoven fields has resulted in a better understanding of a number of diseases related to copper imbalances and current developments might open the path for novel and innovating therapies to address thChemical Communications 01/2015; DOI:10.1039/C4CC10366A · 6.72 Impact Factor