Corticotropin-releasing hormone protects neurons against insults relevant to the pathogenesis of Alzheimer's disease

We previously reported that mice over-expressing the human amyloid precurso r protein gene with the double Swedish mutation of familial Alzheimer's dis ease (mtAPP), which exhibit progressive deposition of amyloid beta -peptide in hippocampal and cortical brain regions, have an impaired ability to mai ntain a sustained glucocorticoid response to stress. Corticotropin releasin g hormone (CRH), which initiates neuroendocrine responses to stress by acti vating the hypothalamic-pituitary-adrenal (HPA) axis, is expressed in brain regions prone to degeneration in Alzheimer's disease. We therefore tested the hypothesis that CRH can modify neuronal vulnerability to amyloid beta - peptide toxicity. In primary neuronal culture, CRH was protective against c ell death caused by an amyloid-beta peptide, an effect that was blocked by a CRH receptor antagonist and by an inhibitor of cyclic AMP-dependent prote in kinase. The increased resistance of CRH-treated neurons to amyloid toxic ity was associated with stabilization of cellular calcium homeostasis. More over, CRH protected neurons against death caused by lipid peroxidation and the excitotoxic neurotransmitter glutamate. The level of mRNA encoding CRH was unchanged in mtAPP mouse brain, whereas the levels of mRNAs encoding gl ucocorticoid and mineralocorticoid receptors were subtly altered. Our resul ts suggest that disturbances in HPA axis function can occur independently o f alterations in CRH mRNA levels in Alzheimer's disease brain and further s uggest an additional role for CRH in protecting neurons against cell death. (C) 2001 Academic Press.