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

Ward A. Pedersen, Deanna McCullers, Carsten Culmsee, Norman J. Haughey, James P. Herman, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

Abstract

We previously reported that mice over-expressing the human amyloid precursor protein gene with the double Swedish mutation of familial Alzheimer's disease (mtAPP), which exhibit progressive deposition of amyloid β-peptide in hippocampal and cortical brain regions, have an impaired ability to maintain a sustained glucocorticoid response to stress. Corticotropin releasing hormone (CRH), which initiates neuroendocrine responses to stress by activating 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 β-peptide toxicity. In primary neuronal culture, CRH was protective against cell death caused by an amyloid-β peptide, an effect that was blocked by a CRH receptor antagonist and by an inhibitor of cyclic AMP-dependent protein kinase. The increased resistance of CRH-treated neurons to amyloid toxicity was associated with stabilization of cellular calcium homeostasis. Moreover, 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 glucocorticoid and mineralocorticoid receptors were subtly altered. Our results suggest that disturbances in HPA axis function can occur independently of alterations in CRH mRNA levels in Alzheimer's disease brain and further suggest an additional role for CRH in protecting neurons against cell death.

Original languageEnglish (US)
Pages (from-to)492-503
Number of pages12
JournalNeurobiology of Disease
Volume8
Issue number3
DOIs
StatePublished - 2001
Externally publishedYes

Keywords

  • Apoptosis
  • Calcium
  • Cyclic AMP
  • Glucocorticoid
  • Glutamate
  • Lipid peroxidation
  • Stress

ASJC Scopus subject areas

  • Neurology

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