Central CRF system perturbation in an Alzheimer's disease knockin mouse model

NEUROBIOLOGY OF AGING

卷:33

Article

Guo, Qinxi^1,2  Zheng, Hui^1,2,3  Justice, Nicholas John^1,3 

[1] Baylor Coll Med, Huffington Ctr Aging, Houston, TX 77030 USA

[2] Baylor Coll Med, Interdept Program Translat Biol & Mol Med, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

关键词: Corticotropin releasing factor;    CRF;    CRH;    CRFR1;    CRHR1;    HPA axis;    Alzheimer's disease;    Corticosteroids;    APP;    Presenilin;    Anxiety;    Depression;   

DOI  :  10.1016/j.neurobiolaging.2012.01.002

来源: Elsevier

【 摘 要 】

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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