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Corticotropin-Releasing Hormone-Mediated Neuroprotection against Oxidative Stress Is Associated with the Increased Release of Non-amyloidogenic Amyloid ß Precursor Protein and with the Suppression of Nuclear Factor-B

Max Planck Institute of Psychiatry 80804 Munich, Germany

The neuropeptide CRH is the central regulator of the hypothalamic-pituitary-adrenal (HPA) stress response system and is implicated in various stress-related conditions. In the neurodegenerative disorder Alzheimer’s disease (AD), levels of CRH are decreased. AD pathology is characterized by the deposition of the nonsoluble amyloid ß protein (Aß), oxidative stress, and neuronal cell death. Employing primary neurons and clonal cells, we demonstrate 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 increased release of non-amyloidogenic soluble Aß precursor protein. At the molecular level CRH caused the suppression of the DNA-binding activity and transcriptional activity of the transcription factor NF-B. Suppression of NF-B by overexpression of a super-repressor mutant form of IB-, a specific inhibitor of NF-B, led to protection of the cells against oxidative stress. These data demonstrate a novel cytoprotective effect of CRH that is mediated by CRH-R1 and downstream by suppression of NF-B and indicate CRH as an endogenous protective neuropeptide against oxidative cell death in addition to its function in the HPA-system. Moreover, the protective function of CRH proposes a molecular link between oxidative stress-related degenerative events and the CRH-R1 system.

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