title: Corticotrophin releasing factor accelerates neuropathology and cognitive decline in a mouse model of Alzheimer's disease.
abstract: Chronic stress has been suggested to influence the pathogenesis of Alzheimer's disease (AD); however, the mechanism underlying this influence remains unknown. In this study, we created a triple transgenic mouse model that overexpresses corticotrophin-releasing factor (CRF) and human amyloid-β protein precursor (AβPP), to investigate whether increases in the expression of CRF can mimic the effects of stress on amyloid metabolism and the neurodegeneration. Tg2576 mice that overexpresses human AβPP gene were crossbreed with Tetop-CRF (CRF) mice and CaMKII-tTA (tTA) mice to create a novel triple transgenic mouse model that conditioned overexpresses CRF in forebrain and overexpresses human AβPP (called AβPP+/CRF+/tTA+, or TT mice). Then we evaluated serial neuro-anatomical and behavioral phenotypes on TT mice using histological, biochemical, and behavioral assays. TT mice showed a Cushingoid-like phenotype starting at 3 months of age. At 6 months of age, these mice demonstrated increases in tissue-soluble amyloid-β (Aβ) and Aβ plaques in the cortex and hippocampus, as compared to control mice. Moreover, TT mice characterized substantial decreases in dendritic branching and dendritic spine density in pyramidal neurons in layer 4 of the frontal cortex and CA1 of the hippocampus. Finally, TT mice showed significantly impaired working memory and contextual memory, with a modest increase in anxiety-like behavior. Our results suggested genetic increases in the brain of CRF expression mimicked chronic stress on the effects of amyloid deposition, neurodegeneration, and behavioral deficits. The novel transgenic mouse model will provide a unique tool to further investigate the mechanisms between stress and AD.
authors: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. h-dong@northwestern.edu
authors: Hongxin
authors: H
authors: Dong
authors: Keely M
authors: KM
authors: Murphy
authors: Liping
authors: L
authors: Meng
authors: Janitza
authors: J
authors: Montalvo-Ortiz
authors: Ziling
authors: Z
authors: Zeng
authors: Benedict J
authors: BJ
authors: Kolber
authors: Shanshan
authors: S
authors: Zhang
authors: Louis J
authors: LJ
authors: Muglia
authors: John G
authors: JG
authors: Csernansky
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D003213:Conditioning, Psychological; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D003623:Dark Adaptation / Q000235:genetics; D049229:Dendritic Spines / Q000473:pathology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000523:psychology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016548:Prosencephalon / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D016622:Silver Staining; D014404:Tubulin / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018019:Receptors, Corticotropin-Releasing Hormone; D014404:Tubulin; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004318:Doxycycline; D003345:Corticosterone