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

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 protein (A), 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 neuroprotec-tion are accompanied by an increased release of non-amyloidogenic soluble A 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-re-pressor mutant form of IB-, a specific inhibitor of NF-B, 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-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 degen-erative events and the CRH-R1 system.