Abstract
To investigate the putative role of β-amyloid peptide (Aβ) in inducing oxidative stress damage in Alzheimer disease (AD), we studied the effects of proinflammatory cytokines and Aβ peptide on the induction of inducible nitric oxide synthase (iNOS). Aβ(25–35) upregulated the cytokine (TNF-α/IL-1 β)-induced expression of iNOS and the production of nitric oxide (NO) in astrocytes, which were inhibited by vitamin E. Aβ treatment of C6 glial cells (together with LPS and IFN-γ), 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-γ, and Aβ(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, NFκB, AP-1, and CREB in C6 glial cells. Hence, these findings suggest a role for ceramide in iNOS induction and NO production in Aβ-induced AD pathobiology and provide a possible explanation for the beneficial effects of vitamin E therapy.
Published Version
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