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 precursor protein gene with the double Swedish mutation of familial Alzheimer's disease (mtAPP), which exhibit progressive deposition of amyloid beta-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 beta-peptide toxicity. In primary neuronal culture, CRH was protective against cell 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 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.
Pedersen
W A
WA
Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, USA.
McCullers
D
D
Culmsee
C
C
Haughey
N J
NJ
Herman
J P
JP
Mattson
M P
MP
D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D005938:Glucocorticoids / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006706:Homeostasis / Q000187:drug effects; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D005938:Glucocorticoids; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D018698:Glutamic Acid; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D002118:Calcium