Abstract
Amyloid β peptide (Aβ) induces hydrogen peroxide (H2O2) and superoxide generation, leading to neuronal death. Many studies have shown the involvement of NADPH oxidase, but the isotype-specific role was not assessed. Moreover, the activation status of phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) 1/2 is unclear in extracellular H2O2 generation. In this paper, we showed that Aβ1-42 induced extracellular H2O2 generation and the resulting cytotoxicity in a concentration-dependent manner. Nox2- and Nox4-specific siRNAs suppressed H2O2 and superoxide generation. LY294002 and U0126, inhibitors of PI3K and ERK1/2, respectively, reduced H2O2 generation in concentration-dependent manners. Furthermore, PI3K activation is responsible for ERK1/2 phosphorylation. An additional increase in H2O2 generation and corresponding cytotoxicity was observed after treatment with Aβ1-42 and glutamate. These results suggest that Aβ1-42 enhances the neuronal vulnerability to oxidative injury in Alzheimer's disease (AD) by increasing H2O2 generation.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Peptides / toxicity
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Animals
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Catalytic Domain / genetics
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Cells, Cultured
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Enzyme Activation
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Extracellular Space / metabolism
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Gene Knockout Techniques
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Glutamic Acid / metabolism
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Glutamic Acid / toxicity
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Hydrogen Peroxide / metabolism*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Mice
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism*
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NADPH Oxidase 2
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NADPH Oxidase 4
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NADPH Oxidases / genetics
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NADPH Oxidases / metabolism
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Neurons / drug effects
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Neurons / metabolism*
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Peptide Fragments / metabolism*
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Peptide Fragments / toxicity
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Primary Cell Culture
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Superoxides / metabolism
Substances
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Amyloid beta-Peptides
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Membrane Glycoproteins
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Peptide Fragments
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Phosphoinositide-3 Kinase Inhibitors
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amyloid beta-protein (1-42)
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Superoxides
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Glutamic Acid
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Hydrogen Peroxide
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Cybb protein, mouse
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NADPH Oxidase 2
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NADPH Oxidase 4
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NADPH Oxidases
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Nox4 protein, mouse
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3