Apoptotic pathways mobilized in microglia and neurones as a consequence ofchromogranin A-induced microglial activation

Senile plaques of Alzheimer's brain are characterized by activated microgli a and immunoreactivity for the peptide chromogranin A. We have investigated the mechanisms by which chromogranin A activates microglia, producing modu lators of neuronal survival. Primary cultures of rat brain-derived microgli a display a reactive phenotype within 24 h of exposure to 10 nM chromograni n A, culminating in microglial death via apoptotic mechanisms mediated by i nterleukin-1 beta converting enzyme. The signalling cascade initiated by ch romogranin A triggers nitric oxide production followed by enhanced microgli al glutamate release, inhibition of which prevents microglial death. The pl asma membrane carrier inhibitor aminoadipate and the type II/III metabotrop ic glutamate receptor antagonist (RS)-alpha-methyl-4-sulphonophenylglycine are equally protective. A significant amount of the released glutamate occu rs from bafilomycin-sensitive stores, suggesting a vesicular mode of releas e. Inhibition of this component of release affords significant microglial p rotection. Conditioned medium from activated microglia kills cerebellar gra nule cells by inducing caspase-3-dependent neuronal apoptosis. Brain-derive d neurotrophic factor is partially neuroprotective, as are ionotropic gluta mate receptor antagonists, and, when combined with boiling of conditioned m edium, full protection is achieved; nitric oxide synthase inhibitors are in effective.