title: Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer's disease-related signaling.
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 CRF1receptor (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 CRF1coupling 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 CRF1signaling. Promotion of AD-related signaling pathways through this mechanism may contribute to female vulnerability to AD.
authors.affiliation: Department of Anesthesiology and Critical Care, The Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, USA.|Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Bangasser
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Carroll
authors.affiliation: Department of Anesthesiology and Critical Care, The Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Plona
authors.affiliation: Proteomics Core, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Rodriguez
authors.affiliation: Proteomics Core, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: McKennan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Csernansky
authors.affiliation: Proteomics Core, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Seeholzer
authors.affiliation: Department of Anesthesiology and Critical Care, The Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Valentino
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D003072:Cognition Disorders / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology; D013315:Stress, Psychological / Q000378:metabolism; D000071560:beta-Arrestin 2 / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D016229:Amyloid beta-Peptides; D018019:Receptors, Corticotropin-Releasing Hormone; D000071560:beta-Arrestin 2; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D053829:Amyloid Precursor Protein Secretases; D019204:GTP-Binding Proteins