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

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    Name:
    Corticotropin-releasing factor ...
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    Genre
    Post-print
    Date
    2017-08-01
    Author
    Bangasser, DA
    Dong, H
    Carroll, J
    Plona, Z
    Ding, H
    Rodriguez, L
    McKennan, C
    Csernansky, JG
    Seeholzer, SH
    Valentino, RJ
    Subject
    Alzheimer Disease
    Amyloid Precursor Protein Secretases
    Amyloid beta-Peptides
    Animals
    Cognition Disorders
    Corticotropin-Releasing Hormone
    Female
    GTP-Binding Proteins
    Humans
    Male
    Mice
    Mice, Transgenic
    Neurons
    Phosphorylation
    Protein Transport
    Receptors, Corticotropin-Releasing Hormone
    Sex Factors
    Signal Transduction
    Stress, Psychological
    beta-Arrestin 2
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    Permanent link to this record
    http://hdl.handle.net/20.500.12613/5004
    
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    DOI
    10.1038/mp.2016.185
    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 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.
    Citation to related work
    Springer Science and Business Media LLC
    Has part
    Molecular Psychiatry
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    ae974a485f413a2113503eed53cd6c53
    http://dx.doi.org/10.34944/dspace/4986
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