Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer's disease-related signaling

D. A. Bangasser, H. Dong, J. Carroll, Z. Plona, H. Ding, L. Rodriguez, C. McKennan, J. G. Csernansky, S. H. Seeholzer, R. J. Valentino*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


Several neuropsychiatric and neurodegenerative disorders share stress as a risk factor and are more prevalent in women than in men. Corticotropin-releasing factor (CRF) orchestrates the stress response, and excessive CRF is thought to contribute to the pathophysiology of these diseases. We previously found that the CRF 1 receptor (CRF 1) is sex biased whereby coupling to its GTP-binding protein, Gs, is greater in females, whereas β-arrestin-2 coupling is greater in males. This study used a phosphoproteomic approach in CRF-overexpressing (CRF-OE) mice to test the proof of principle that when CRF is in excess, sex-biased CRF 1 coupling translates into divergent cell signaling that is expressed as different brain phosphoprotein profiles. Cortical phosphopeptides that distinguished female and male CRF-OE mice were overrepresented in unique pathways that were consistent with Gs-dependent signaling in females and β-arrestin-2 signaling in males. Notably, phosphopeptides that were more abundant in female CRF-OE mice were overrepresented in an Alzheimer's disease (AD) pathway. Phosphoproteomic results were validated by demonstrating that CRF overexpression in females was associated with increased tau phosphorylation and, in a mouse model of AD pathology, phosphorylation of β-secretase, the enzyme involved in the formation of amyloid β. These females exhibited increased formation of amyloid β plaques and cognitive impairments relative to males. Collectively, the findings are consistent with a mechanism whereby the excess CRF that characterizes stress-related diseases initiates distinct cellular processes in male and female brains, as a result of sex-biased CRF 1 signaling. Promotion of AD-related signaling pathways through this mechanism may contribute to female vulnerability to AD.

Original languageEnglish (US)
Pages (from-to)1126-1133
Number of pages8
JournalMolecular Psychiatry
Issue number8
StatePublished - Aug 1 2017

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Molecular Biology


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