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The Journal of Neuroscience, May 1, 1998, 18(9):3224-3232

High Constitutive NF-kappa B Activity Mediates Resistance to Oxidative Stress in Neuronal Cells

Frank Lezoualc'h1, Yutaka Sagara2, Florian Holsboer1, and Christian Behl1

1 Max-Planck-Institute of Psychiatry, 80804 Munich, Germany, and 2 The Salk Institute for Biological Studies, San Diego, California 90370

Selected clones of the sympathetic precursor-like cell line PC12 (rCl8) are resistant to oxidative cell death induced by the Alzheimer's disease-associated amyloid beta  protein (Abeta ) and hydrogen peroxide (H2O2). Here, we show that the transcriptional activity and DNA binding activity of the redox-sensitive transcription factor NF-kappa B and its nuclear expression are constitutively increased in rCl8 cells compared with their nonresistant parental PC12 cell (PC12p) counterpart. Suppression of the transcriptional activity of NF-kappa B in rCl8 cells with the synthetic glucocorticoid dexamethasone or by direct overexpression of a super-repressor mutant form of Ikappa Balpha , a specific inhibitor of NF-kappa B, reversed the oxidative stress resistance phenotype of these cells and ultimately led to increased cell death after the challenge with H2O2. Dexamethasone treatment also caused an increase in the protein level of Ikappa Balpha . Our data show that an increased baseline of NF-kappa B activity may mediate the resistance of these cells of neuronal origin to oxidative stress. Therefore, the presented model may help to identify possible neuronal target genes of NF-kappa B and to further elucidate the molecular basis of the differential sensitivity of neurons in neurodegenerative conditions associated with an increased oxidative burden, such as in Alzheimer's disease.

Key words: NF-kappa B; Alzheimer's disease; amyloid beta  protein; oxidative stress; antioxidant enzymes; glucocorticoids; neuroprotection


Copyright © 1998 Society for Neuroscience  0270-6474/98/1893224-09$05.00/0


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