MICROGLIAL RELEASE OF NITRIC-OXIDE BY THE SYNERGISTIC ACTION OF BETA-AMYLOID AND IFN-GAMMA

Alzheimer's disease (AD) is a progressive neurodegenerative disorder c haracterized histopathologically by a loss of neurons and an accumulat ion of beta-amyloid plaques, neurofibrillary tangles, dystrophic neuri tes, and reactive glial cells. While most previous studies on the neur odegeneration of AD have focused on neuronal cells and direct beta-amy loid-mediated neurotoxicity, few have focused on the role of reactive glial cells in beta-amyloid-mediated neurotoxicity. In the present stu dy nitric oxide release from cultured rat microglia was examined by ex posing the cells to synthetic beta-amyloid peptides (beta 25-35 and be ta 1-40) alone and in combination with the cytokines IFN-alpha/beta (1 00 U/ml), IL-1 beta (100 U/ml), TNF-alpha (100 U/ml), TNF-beta (100 U/ ml), or IFN-gamma (10, 100, 500, or 1000 U/ml). Assessment of microgli al release of nitric oxide was based on the colorimetric assay for nit rite in the culture medium and histochemistry for nitric oxide synthas e. Of the cytokines tested, only IFN-gamma (1000 U/ml) induced nitric oxide release from microglia. beta 25-35 did not stimulate nitric oxid e release by itself, but it did induce nitric oxide release when co-ex posed with IFN-gamma (100, 500, and 1000 U/ml). In contrast, beta 1-40 did induce microglial release of nitric oxide by itself, and this eff ect was enhanced significantly by co-exposure with IFN-gamma (100 U/ml ). These findings warrant a further investigation into the role of mic roglia in the neurodegeneration of Alzheimer's disease via nitric oxid e toxicity induced by the synergistic action of P-amyloid and a costim ulatory factor.