TY - JOUR
T1 - Corticotrophin releasing factor accelerates neuropathology and cognitive decline in a mouse model of Alzheimer's disease
AU - Dong, Hongxin
AU - Murphy, Keely M.
AU - Meng, Liping
AU - Montalvo-Ortiz, Janitza
AU - Zeng, Ziling
AU - Kolber, Benedict J.
AU - Zhang, Shanshan
AU - Muglia, Louis J.
AU - Csernansky, John G.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - amyloid-β
KW - cognitive function
KW - corticotrophin- releasing factor
KW - neurodegeneration
KW - stress
UR - http://www.scopus.com/inward/record.url?scp=84863295841&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863295841&partnerID=8YFLogxK
U2 - 10.3233/JAD-2011-111328
DO - 10.3233/JAD-2011-111328
M3 - Article
C2 - 22045495
AN - SCOPUS:84863295841
VL - 28
SP - 579
EP - 592
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 3
ER -