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

Molecular Psychiatry volume 22, pages 1126–1133 (2017)Cite this article

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Abstract

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 CRF1 receptor (CRF1) 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 CRF1 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 CRF1 signaling. Promotion of AD-related signaling pathways through this mechanism may contribute to female vulnerability to AD.

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Acknowledgements

This work was supported by an NIH Grants MH040008, MH092438, AG25824 and HD026979, and a Foederer Foundation grant and a grant from the UPenn Comprehensive Neuroscience Center. Special thanks to Lynn A Spruce for her tireless expert assistance with mass spectrometry and to Harry Ischiroupoulos for advice and comments on the manuscript.

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Authors and Affiliations

  1. Department of Anesthesiology and Critical Care, The Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, USA

    D A Bangasser, Z Plona & R J Valentino

  2. Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA, USA

    D A Bangasser

  3. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    H Dong, L Rodriguez & J G Csernansky

  4. Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA, USA

    J Carroll

  5. Proteomics Core, The Children's Hospital of Philadelphia, Philadelphia, PA, USA

    H Ding, C McKennan & S H Seeholzer

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  1. D A Bangasser
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Correspondence to R J Valentino.

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Bangasser, D., Dong, H., Carroll, J. et al. Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer’s disease-related signaling. Mol Psychiatry 22, 1126–1133 (2017). https://doi.org/10.1038/mp.2016.185

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