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

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Abstract
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 neurodegenera- tive disorder Alzheimer's disease (AD), levels of CRH are decreased. AD pathology is characterized by the deposition of the nonsoluble amyloid b pro- tein (Ab), oxidative stress, and neuronal cell death. Employing primary neurons and clonal cells, we demonstrate that CRH has a neuroprotective ac- tivity in CRH-receptor type 1 (CRH-R1)-expressing neurons against oxidative cell death. The protec- tive 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 neuroprotec- tion are accompanied by an increased release of non-amyloidogenic soluble Ab precursor protein. At the molecular level CRH caused the suppression of the DNA-binding activity and transcriptional ac- tivity of the transcription factor NF-kB. Suppres- sion of NF-kB by overexpression of a super-re- pressor mutant form of IkB-a, a specific inhibitor of NF-kB, led to protection of the cells against oxida- tive stress. These data demonstrate a novel cyto- protective effect of CRH that is mediated by CRH-R1 and downstream by suppression of NF-kB and indicate CRH as an endogenous protective neuropeptide against oxidative cell death in addi- tion to its function in the HPA-system. Moreover, the protective function of CRH proposes a molec- ular link between oxidative stress-related degen-

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