Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer's disease-related signaling
Genre
Post-printDate
2017-08-01Author
Bangasser, DADong, H
Carroll, J
Plona, Z
Ding, H
Rodriguez, L
McKennan, C
Csernansky, JG
Seeholzer, SH
Valentino, RJ
Subject
Alzheimer DiseaseAmyloid 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
Permanent link to this record
http://hdl.handle.net/20.500.12613/5004
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10.1038/mp.2016.185Abstract
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
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http://dx.doi.org/10.34944/dspace/4986