Inflammatory mediator and beta-amyloid (25-35)-induced ceramide generation and iNOS expression are inhibited by...

To investigate the putative role of beta-amyloid peptide (A beta) in inducing oxidative stress damage in Alzheimer disease (AD), we studied the effects of proinflammatory cytokines and A beta peptide on the induction of inducible nitric oxide synthase (iNOS). A beta(25-35) upregulated the cytokine (TNF-alpha/IL-1 beta)-induced expression of iNOS and the production of nitric oxide (NO) in astrocytes, which were inhibited by vitamin E. A beta treatment of C6 glial cells (together with LPS and IFN-gamma), in addition to inducing iNOS, enhanced the oxidative stress as measured by increased expression of manganese superoxide dismutase and an increase in 2,7'-dichlorofluorescein diacetate fluorescence. We also observed that LPS, IFN-gamma, and A beta(25-35) treatment led to the activation of the sphingomyelin-ceramide (SM-Cer) cascade with an increase in cellular ceramide. Inhibition of the SM-Cer cascade either by vitamin E treatment or by the neutral sphingomyelinase inhibitor 3-O-methyl sphingomyelin also resulted in alteration of the transcriptional binding activities of C/EBP, NFkappaB, AP-1, and CREB in C6 glial cells. Hence, these findings suggest a role for ceramide in iNOS induction and NO production in Abeta-induced AD pathobiology and provide a possible explanation for the beneficial effects of vitamin E therapy.