beta-amyloid activates the O-2 forming NADPH oxidase in microglia, monocytes, and neutrophils. A possible inflammatory mechanism of neuronal damage in Alzheimer's disease.
The deposition of beta-amyloid in the brain is the key pathogenetic event in Alzheimer's disease. Among the various mechanisms proposed to explain the neurotoxicity of beta-amyloid deposits, a new one, recently identified in our and other laboratories, suggests that beta-amyloid is indirectly neurotoxic by activating microglia to produce toxic inflammatory mediators such as cytokines, nitric oxide, and oxygen free radicals. Three findings presented here support this mechanism, showing that beta-amyloid peptides (25-35), (1-39), and (1-42) activated the classical NADPH oxidase in rat primary culture of microglial cells and human phagocytes: 1) The exposure of the cells to beta-amyloid peptides stimulates the production of reactive oxygen intermediates; 2) the stimulation is associated with the assembly of the cytosolic components of NADPH oxidase on the plasma membrane, the process that corresponds to the activation of the enzyme; 3) neutrophils and monocytes of chronic granulomatous disease patients do not respond to beta-amyloid peptides with the stimulation of reactive oxygen intermediate production. Data are also presented that the activation of NADPH oxidase requires that beta-amyloid peptides be in fibrillary state, is inhibited by inhibitors of tyrosine kinases or phosphatidylinositol 3-kinase and by dibutyryl cyclic AMP, and is potentiated by interferon-gamma or tumor necrosis factor-alpha.
Bianca
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VD
Institute of General Pathology, University of Verona, 37134 Verona, Italy.
Dusi
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S
Bianchini
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Dal Prà
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I
Rossi
F
F
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation; D006497:Heparan Sulfate / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D017628:Microglia / Q000201:enzymology*; D009000:Monocytes / Q000201:enzymology*; D019255:NADPH Oxidases / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D003994:Bucladesine; D006497:Heparan Sulfate; D006861:Hydrogen Peroxide; D007371:Interferon-gamma; D019255:NADPH Oxidases; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha