title: Central CRF system perturbation in an Alzheimer's disease knockin mouse model.
abstract: 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 (hAβ), and presenilin 1 (PS1), in their endogenous patterns (APP/hAβ/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/hAβ/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/hAβ/PS1 mice, suggesting that perturbations of the CRF system are not the primary cause of decreased cognitive performance.
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Qinxi
authors.initials: Q
authors.lastname: Guo
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Nicholas John
authors.initials: NJ
authors.lastname: Justice
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D010913:Pituitary-Adrenal System / Q000378:metabolism* / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D000099052:CRF Receptor, Type 1
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone