The effects of nerve growth factor and nitric oxide synthase inhibitors on amyloid precursor protein expression

NGF can regulate nitric oxide synthase (NOS) expression and nitric oxide (NO) can modulate NGF-mediated neurotrophic responses. In this study the role of NO in NGF-stimulated expression of amyloid precursor protein (APP) was studied. PC12 cells were treated with either the nonselective inhibitor (L-NAME) or the inducible NOS selective inhibitor (S-MIU), and the effect on NGF-activated APP levels was determined. NGF significantly increased total APP protein levels by 96 hours, while decreasing mRNA expression significantly from control at all time points studied. Various concentrations of S-MIU, and 20.0 mM L-NAME blocked the induction of amyloid precursor protein expression in PC12 cells. Treatment with S-MIU alone or in the presence of NGF decreased APP mRNA below control while only L-NAME in the presence of NGF reduced the level of APP mRNA. NGF-mediated induction in APP promoter activity was inhibited by S-MIU, but increased by L-NAME. S-MIU prolonged the activation of pAkt while L-NAME exhibited no effect. The MAPK and Akt pathway inhibitors blocked the NGF-mediated stimulation of APP. This study indicates that NO is involved in the induction of APP via NGF-mediated pathways.