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Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer's disease-related signaling.
- Source :
-
Molecular psychiatry [Mol Psychiatry] 2017 Aug; Vol. 22 (8), pp. 1126-1133. Date of Electronic Publication: 2016 Oct 18. - Publication Year :
- 2017
-
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 <subscript>1</subscript> receptor (CRF <subscript>1</subscript> ) 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 <subscript>1</subscript> 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 <subscript>1</subscript> signaling. Promotion of AD-related signaling pathways through this mechanism may contribute to female vulnerability to AD.
- Subjects :
- Alzheimer Disease metabolism
Amyloid Precursor Protein Secretases metabolism
Amyloid beta-Peptides metabolism
Animals
Cognition Disorders metabolism
Female
Humans
Male
Mice
Mice, Transgenic
Neurons metabolism
Phosphorylation
Protein Transport physiology
Sex Factors
Signal Transduction physiology
Stress, Psychological metabolism
beta-Arrestin 2 metabolism
Corticotropin-Releasing Hormone metabolism
GTP-Binding Proteins metabolism
Receptors, Corticotropin-Releasing Hormone metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5578
- Volume :
- 22
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Molecular psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 27752081
- Full Text :
- https://doi.org/10.1038/mp.2016.185