Abstract
Chromogranin A is up-regulated in the senile plaques of Alzheimer's brain and is a novel activator of microglia, transforming them to a neurotoxic phenotype. Treatment of primary cultures of rat brain microglia or the murine N9 microglial cell line with chromogranin A resulted in nitric oxide production, which triggered microglial apoptosis. Exposure of microglia to chromogranin A resulted in a fall in mitochondrial membrane potential. Mitochondrial depolarisation and apoptosis were reduced significantly by cyclosporin A, but not by the calcineurin inhibitor FK506. Cytochrome c did not translocate from the mitochondria to the cytosol, but its expression became significantly enhanced within the mitochondria. Inhibition of caspase 1 attenuated chromogranin A-induced microglial apoptosis, but did not prevent mitochondrial depolarisation, indicating that apoptosis occurred downstream of mitochondrial depolarisation. Conversely, staurosporine-induced microglial apoptosis led to mitochondrial cytochrome c release, but not caspase 1 activation. Our findings provide insight into the pathways controlling activation-triggered microglial apoptosis and may point to routes for the modulation of microglial evoked neurotoxicity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Diphosphate / metabolism
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Adenosine Triphosphate / metabolism
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Animals
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Apoptosis / drug effects*
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Biomarkers, Tumor / pharmacology*
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Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology
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Caspase 1 / metabolism
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Cell Membrane Permeability / drug effects
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Cell Membrane Permeability / physiology
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Cells, Cultured
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Chromogranin A
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Chromogranins / pharmacology*
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Cysteine Proteinase Inhibitors / pharmacology
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Cytochrome c Group / metabolism*
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Cytosol / metabolism
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Enzyme Inhibitors / pharmacology
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Microglia / cytology*
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Microglia / enzymology
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Nitric Oxide / metabolism
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Nitric Oxide Synthase / metabolism
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Oligopeptides / pharmacology
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Rats
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Staurosporine / pharmacology
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Uncoupling Agents / pharmacology
Substances
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Biomarkers, Tumor
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Chromogranin A
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Chromogranins
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Cysteine Proteinase Inhibitors
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Cytochrome c Group
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Enzyme Inhibitors
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Oligopeptides
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Uncoupling Agents
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benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
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chromogranin A, rat
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L 709049
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Nitric Oxide
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Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
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Adenosine Diphosphate
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Adenosine Triphosphate
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Nitric Oxide Synthase
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Caspase 1
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Staurosporine