Overexpression of amyloid precursor protein is associated with degeneration, decreased viability, and increased damage caused by neurotoxins (prostaglandins A1 and E2, hydrogen peroxide, and nitric oxide) in differentiated neuroblastoma cells

• Published in: Journal of neuroscience research 2003-10, Vol.74 (1), p.148-159
• Main Authors: Hanson, Amy J., Prasad, Judith E., Nahreini, Piruz, Andreatta, Cynthia, Kumar, Bipin, Yan, Xiang-Dong, Prasad, Kedar N.
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid beta-Protein Precursor - biosynthesis; Amyloid beta-Protein Precursor - genetics; amyloid precursor protein; Animals; Cell Differentiation - drug effects; Cell Line; Cell Survival - drug effects; Cell Survival - genetics; differentiated neuroblastoma cells; Dinoprostone - toxicity; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Down-Regulation - genetics; Gene Expression Regulation - physiology; Humans; hydrogen peroxide; Hydrogen Peroxide - toxicity; Mice; Nerve Degeneration - genetics; Nerve Degeneration - pathology; Neuroblastoma - genetics; Neuroblastoma - pathology; Neurotoxins - toxicity; Nitric Oxide - toxicity; nitric oxide donor; prostaglandin; Prostaglandins A - toxicity; Tumor Cells, Cultured; β-amyloid
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.10726

Inflammatory reactions are considered one of the important etiologic factors in the pathogenesis of Alzheimer's disease (AD). Prostaglandins such as PGE2 and PGA1 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 β‐amyloid fragments (Aβ40 and Aβ42), 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 Aβ40 and Aβ42. PGA1 or PGE2 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 Aβ40 and Aβ42, or proteasome activity. H2O2 or SIN‐1 (an NO donor) treatment did not change vector‐derived APP mRNA levels, but H2O2 reduced the level of human APP protein more than SIN‐1. Furthermore, SIN‐1 increased the secreted level of Aβ40, but not of Aβ42, whereas H2O2 had no effect on the level of secreted Aβ fragments. Both H2O2 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 H2O2 and SIN‐1 and that the mechanisms of neurotoxicity of H2O2 and SIN‐1 are, at least in part, different from each other. © 2003 Wiley‐Liss, Inc.