期刊
NEUROBIOLOGY OF AGING
卷 33, 期 11, 页码 2678-2691出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2012.01.002
关键词
Corticotropin releasing factor; CRF; CRH; CRFR1; CRHR1; HPA axis; Alzheimer's disease; Corticosteroids; APP; Presenilin; Anxiety; Depression
资金
- Eunice Kennedy Shriver NICHD/NIH [U54-HD28934]
- NIH [K01AG036738]
- ADMDC Mitchell Pilot Grant
- [R01AG020670]
- [R01AG032051]
- [R01AG035467]
Alzheimer's disease (AD) is often accompanied by changes in mood as well as increases in circulating cortisol levels, suggesting that regulation of the stress responsive hypothalamic-pituitary-adrenal (HPA) axis is disturbed. Here, we show that amyloid precursor protein (APP) is endogenously expressed in important limbic, hypothalamic, and midbrain nuclei that regulate hypothalamic-pituitary-adrenal axis activity. Furthermore, in a knockin mouse model of AD that expresses familial AD (FAD) mutations of both APP with humanized amyloid beta (hA beta), and presenilin 1 (PS1), in their endogenous patterns (APP/hA beta/PS1 animals), corticotropin releasing factor (CRF) levels are increased in key stress-related nuclei, resting corticosteroid levels are elevated, and animals display increased anxiety-related behavior. Endocrine and behavioral phenotypes can be normalized by loss of 1 copy of CRF receptor type-1 (Crfr1), consistent with a perturbation of central CRF signaling in APP/hA beta/PS1 animals. However, reductions in anxiety and corticosteroid levels conferred by heterozygosity of CRF receptor type-1 do not improve a deficit in working memory observed in APP/hA beta/PS1 mice, suggesting that perturbations of the CRF system are not the primary cause of decreased cognitive performance. (C) 2012 Elsevier Inc. All rights reserved.
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