Microglial apoptosis induced by chromogranin A is mediated by mitochondrial depolarisation and the permeability transition but not by cytochrome c release.
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.
Kingham
P J
PJ
Department of Neurochemistry, Institute of Neurology, University College London, England.
Pocock
J M
JM
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000494:pharmacology*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D020170:Caspase 1 / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D053379:Chromogranin A; D002864:Chromogranins / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D017628:Microglia / Q000166:cytology* / Q000201:enzymology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D014408:Biomarkers, Tumor; D053379:Chromogranin A; D002864:Chromogranins; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D014475:Uncoupling Agents; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C506153:chromogranin A, rat; C096429:L 709049; D009569:Nitric Oxide; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D020170:Caspase 1; D019311:Staurosporine