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Overexpression of amyloid precursor protein is associated with degeneration, decreased viability, and increased damage caused by neurotoxins (prostaglandins A 1 and E 2 , hydrogen peroxide, and nitric oxide) in differentiated neuroblastoma cells
Author(s) -
Hanson Amy J.,
Prasad Judith E.,
Nahreini Piruz,
Andreatta Cynthia,
Kumar Bipin,
Yan XiangDong,
Prasad Kedar N.
Publication year - 2003
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10726
Subject(s) - neurodegeneration , viability assay , nitric oxide , oxidative stress , amyloid precursor protein , chemistry , proteasome , endocrinology , medicine , microbiology and biotechnology , cell , biochemistry , biology , alzheimer's disease , disease
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 β‐amyloid fragments (Aβ 40 and Aβ 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 Aβ 40 and Aβ 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 Aβ 40 and Aβ 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 Aβ 40 , but not of Aβ 42 , whereas H 2 O 2 had no effect on the level of secreted Aβ 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 neurotoxicity of H 2 O 2 and SIN‐1 are, at least in part, different from each other. © 2003 Wiley‐Liss, Inc.