Apoptotic pathways mobilized in microglia and neurones as a consequence of chromogranin A-induced microglial activation.
Senile plaques of Alzheimer's brain are characterized by activated microglia and immunoreactivity for the peptide chromogranin A. We have investigated the mechanisms by which chromogranin A activates microglia, producing modulators of neuronal survival. Primary cultures of rat brain-derived microglia display a reactive phenotype within 24 h of exposure to 10 nM chromogranin A, culminating in microglial death via apoptotic mechanisms mediated by interleukin-1beta converting enzyme. The signalling cascade initiated by chromogranin A triggers nitric oxide production followed by enhanced microglial glutamate release, inhibition of which prevents microglial death. The plasma membrane carrier inhibitor aminoadipate and the type II/III metabotropic glutamate receptor antagonist (RS)-alpha-methyl-4-sulphonophenylglycine are equally protective. A significant amount of the released glutamate occurs from bafilomycin-sensitive stores, suggesting a vesicular mode of release. Inhibition of this component of release affords significant microglial protection. Conditioned medium from activated microglia kills cerebellar granule cells by inducing caspase-3-dependent neuronal apoptosis. Brain-derived neurotrophic factor is partially neuroprotective, as are ionotropic glutamate receptor antagonists, and, when combined with boiling of conditioned medium, full protection is achieved; nitric oxide synthase inhibitors are ineffective.
Kingham
P J
PJ
Department of Neurochemistry, Institute of Neurology, University College London, England, UK.
Cuzner
M L
ML
Pocock
J M
JM
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D048429:Cell Size / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D053379:Chromogranin A; D002864:Chromogranins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D018698:Glutamic Acid / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017628:Microglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019335:Nitroarginine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats
D015415:Biomarkers; D061945:Caspase Inhibitors; D053379:Chromogranin A; D002864:Chromogranins; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D009498:Neurotoxins; D009842:Oligopeptides; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C506153:chromogranin A, rat; C096429:L 709049; D019335:Nitroarginine; D009569:Nitric Oxide; D018698:Glutamic Acid; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1