Corticotropin-releasing hormone mediated neuroprotection against oxidativestress is associated with the increased release of non amyloidogenic amyloid beta precursor protein and with the suppression of nuclear factor-kappa B

Citation
F. Lezoualc'H et al., Corticotropin-releasing hormone mediated neuroprotection against oxidativestress is associated with the increased release of non amyloidogenic amyloid beta precursor protein and with the suppression of nuclear factor-kappa B, MOL ENDOCR, 14(1), 2000, pp. 147-159
Citations number
61
Categorie Soggetti
Endocrinology, Nutrition & Metabolism
Journal title
MOLECULAR ENDOCRINOLOGY
ISSN journal
08888809 → ACNP
Volume
14
Issue
1
Year of publication
2000
Pages
147 - 159
Database
ISI
SICI code
0888-8809(200001)14:1<147:CHMNAO>2.0.ZU;2-W
Abstract
The neuropeptide CRH is the central regulator of the hypothalamic-pituitary -adrenal (HPA) stress response system and is implicated in various stress-r elated conditions. In the neurodegenerative disorder Alzheimer's disease (A D), levels of CRH are decreased. AD pathology is characterized by the depos ition of the nonsoluble amyloid beta protein (A beta), oxidative stress, an d neuronal cell death. Employing primary neurons and clonal cells, we demon strate that CRH has a neuroprotective activity in CRH-receptor type 1 (CRH- R1)-expressing neurons against oxidative cell death. The protective effect of CRH was blocked by selective and nonselective CRH-R1 antagonists and by protein kinase A inhibitors. Overexpression of CRH-R1 in clonal hippocampal cells lacking endogenous CRH-receptors established neuroprotection by CRH. The activation of CRH-R1 and neuroprotection are accompanied by an increas ed release of non-amyloidogenic soluble A beta precursor protein. At the mo lecular level CRH caused the suppression of the DNA-binding activity and tr anscriptional activity of the transcription factor NF-kappa B. Suppression of NF-kappa B by overexpression of a super-repressor mutant form of I kappa B-alpha, a specific inhibitor of NF-kappa B, led to protection of the cell s against oxidative stress. These data demonstrate a novel cytoprotective e ffect of CRH that is mediated by CRH-R1 and downstream by suppression of NF -kappa B and indicate CRH as an endogenous protective neuropeptide against oxidative cell death in addition to its function in the HPA-system. Moreove r, the protective function of CRH proposes a molecular link between oxidati ve stress-related degenerative events and the CRH-R1 system.