Inflammatory reactions are considered one of the important etiologic factors in the pathogenesis of Alzheimer's disease (AD). Prostaglandins such as PGE 2 and PGA 1 and free radicals are some of the agents released during inflammatory reactions, and they are neurotoxic. The mechanisms of their action are not well understood. Increased levels of -amyloid fragments (A 40 and A 42 ), generated through cleavage of amyloid precursor protein (APP), oxidative stress, and proteasome inhibition, are also associated with neurodegeneration in AD brains. Therefore, we investigated the effect of PGs and oxidative stress on the degeneration and viability of cyclic AMP-induced differentiated NB cells overexpressing wild-type APP (NBP2-PN46) under the control of the CMV promotor in comparison with differentiated vector (NBP2-PN1) or parent (NBP2) control cells. Results showed that differentiated NBP2-PN46 cells exhibited enhanced spontaneous degeneration and decreased viability in comparison with differentiated control cells, without changing the level of A 40 and A 42 . PGA 1 or PGE 2 treatment of differentiated cells caused increased degeneration and reduced viability in all three cell lines. These effects of PGs are not due to alterations in the levels of vector-derived APP mRNA or human APP holoprotein, secreted levels of A 40 and A 42 , or proteasome activity. H 2 O 2 or SIN-1 (an NO donor) treatment did not change vector-derived APP mRNA levels, but H 2 O 2 reduced the level of human APP protein more than SIN-1. Furthermore, SIN-1 increased the secreted level of A 40 , but not of A 42 , whereas H 2 O 2 had no effect on the level of secreted A fragments. Both H 2 O 2 and SIN-1 inhibited proteasome activity in the intact cells. The failure of neurotoxins to alter APP mRNA levels could be due to the fact that they do not affect CMV promoter activity. These results suggest that the mechanisms of action of PGs on neurodegeneration are different from those of H 2 O 2 and SIN-1 and that the mechanisms of neurotox-icity of H 2 O 2 and SIN-1 are, at least in part, different from each other.