CHROMOGRANIN-A INDUCES A NEUROTOXIC PHENOTYPE IN BRAIN MICROGLIAL CELLS

Chromogranin A (CGA) belongs to a multifunctional protein family widel y distributed in secretory vesicles in neurons and neuroendocrine cell s. Within the brain, CGA is localized in neurodegenerative areas assoc iated with reactive microglia. By using cultured rodent microglia, we recently described that CGA induces an activated phenotype and the gen eration of nitric oxide. These findings led us to examine whether CGA might affect neuronal survival, expression of neurofilaments, and high affinity gamma-aminobutyric acid uptake in neurons cultured in the pr esence or absence of microglial cells. We found that CGA was unable to exert a direct toxic effect on neurons but provoked neuronal injury a nd degeneration in the presence of microglial cells. These effects wer e observed with natural and recombinant CGA and with a recombinant N-t erminal fragment corresponding to residues 1-78. CGA stimulated microg lial cells to secrete heat-stable diffusible neurotoxic agents. CGA al so induced a marked accumulation of nitric oxide and tumor necrosis fa ctor-alpha by microglia, but we could not establish a direct correlati on between the levels of nitric oxide and tumor necrosis factor-alpha and the neuronal damage. The possibility that CGA represents an endoge nous factor that triggers the microglial responses responsible for the pathogenesis of neuronal degeneration is discussed.