Premium
Microglial Apoptosis Induced by Chromogranin A Is Mediated by Mitochondrial Depolarisation and the Permeability Transition but Not by Cytochrome c Release
Author(s) -
Kingham Paul J.,
Pocock Jennifer M.
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0741452.x
Subject(s) - cytochrome c , mitochondrial permeability transition pore , microglia , apoptosis , mitochondrion , microbiology and biotechnology , mitochondrial apoptosis induced channel , chromogranin a , biology , depolarization , apoptosome , programmed cell death , caspase , chemistry , biochemistry , endocrinology , inflammation , immunology , immunohistochemistry
Chromogranin A is up‐regulated in the senile plaques ofAlzheimer's brain and is a novel activator of microglia, transforming them toa neurotoxic phenotype. Treatment of primary cultures of rat brain microgliaor the murine N9 microglial cell line with chromogranin A resulted in nitricoxide production, which triggered microglial apoptosis. Exposure of microgliato chromogranin A resulted in a fall in mitochondrial membrane potential.Mitochondrial depolarisation and apoptosis were reduced significantly bycyclosporin A, but not by the calcineurin inhibitor FK506. Cytochrome c did not translocate from the mitochondria to the cytosol, but itsexpression became significantly enhanced within the mitochondria. Inhibitionof caspase 1 attenuated chromogranin A‐induced microglial apoptosis, but didnot prevent mitochondrial depolarisation, indicating that apoptosis occurreddownstream of mitochondrial depolarisation. Conversely, staurosporine‐inducedmicroglial 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.