Corticotrophin releasing factor accelerates neuropathology and cognitive decline in a mouse model of Alzheimer's disease

Hongxin Dong*, Keely M. Murphy, Liping Meng, Janitza Montalvo-Ortiz, Ziling Zeng, Benedict J. Kolber, Shanshan Zhang, Louis J. Muglia, John G. Csernansky

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)579-592
Number of pages14
JournalJournal of Alzheimer's Disease
Issue number3
StatePublished - 2012


  • Alzheimer's disease
  • amyloid-β
  • cognitive function
  • corticotrophin- releasing factor
  • neurodegeneration
  • stress

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Clinical Psychology
  • General Neuroscience


Dive into the research topics of 'Corticotrophin releasing factor accelerates neuropathology and cognitive decline in a mouse model of Alzheimer's disease'. Together they form a unique fingerprint.

Cite this