Mechanisms underlying neuronal death induced by chromogranin A-activated microglia

The neurotoxic effects of activated microglia in neurodegenerative diseases are well established. We recently provided evidence that chromogranin A (C GA), a multifunctional protein localized in dystrophic neurites and in seni le plaques, induces an activated phenotype and secretion of neurotoxins by rat microglia in culture. In the present study, we focused on the mechanism s underlying neuronal degeneration triggered by CGA-activated microglia, We found that neuronal death exhibits apoptotic features, characterized by th e externalization of phosphatidylserine and the fragmentation of DNA. Micro glial neurotoxins markedly stimulate the phosphorylation and activity of ne uronal p38 mitogen-activated protein kinase and provoke the release of mito chondrial cytochrome c, which precedes apoptosis. Inhibition of p38 kinase with SE 203580 partially protects neurons from death induced by CGA-activat ed microglia. Furthermore, neurons are also protected by Fas-Fc, which anta gonizes the interactions between the death receptor Fas and its ligand Fast and by cell-permeable peptides that inhibit caspases 8 and 3. Thus, CGA tr iggers the release of microglial neurotoxins that mobilize several death-si gnaling pathways in neurons. Our results further support the idea that CGA, which is upregulated in many neuropathologies, represents a potent endogen eous inflammatory factor possibly responsible for neuronal degeneration.