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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 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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References

  1. Breslau N . Gender differences in trauma and posttraumatic stress disorder. J Gend Specif Med 2002; 5: 34–40.

    PubMed  Google Scholar 

  2. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994; 51: 8–19.

    CAS  Article  PubMed  Google Scholar 

  3. Gao S, Hendrie HC, Hall KS, Hui S . The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis. Arch Gen Psychiatry 1998; 55: 809–815.

    CAS  Article  PubMed  Google Scholar 

  4. Ruitenberg A, Ott A, van Swieten JC, Hofman A, Breteler MM . Incidence of dementia: does gender make a difference? Neurobiol Aging 2001; 22: 575–580.

    CAS  Article  PubMed  Google Scholar 

  5. Wilson RS, Arnold SE, Schneider JA, Kelly JF, Tang Y, Bennett DA . Chronic psychological distress and risk of Alzheimer's disease in old age. Neuroepidemiology 2006; 27: 143–153.

    Article  PubMed  Google Scholar 

  6. Vale W, Spiess J, Rivier C, Rivier J . Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 1981; 213: 1394–1397.

    CAS  Article  PubMed  Google Scholar 

  7. Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM et al. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 1997; 154: 624–629.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Nemeroff C, Widerlov E, Bissette GT, Walleus H, Karlson I, Eklund K et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984; 226: 1342–1344.

    CAS  Article  PubMed  Google Scholar 

  9. Leake A, Perry EK, Perry RH, Fairbairn AF, Ferrier IN . Cortical concentrations of corticotropin-releasing hormone and its receptor in Alzheimer type dementia and major depression. Biol Psychiatry 1990; 28: 603–608.

    CAS  Article  PubMed  Google Scholar 

  10. Bangasser DA, Curtis A, Reyes BA, Bethea TT, Parastatidis I, Ischiropoulos H et al. Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology. Mol Psychiatry 2010; 15: 877, 896–904.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Curtis AL, Bethea T, Valentino RJ . Sexually dimorphic responses of the brain norepinephrine system to stress and corticotropin-releasing factor. Neuropsychopharmacology 2006; 31: 544–554.

    CAS  Article  PubMed  Google Scholar 

  12. Bangasser DA, Reyes BA, Piel D, Garachh V, Zhang XY, Plona ZM et al. Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression. Mol Psychiatry 2012; 18: 166–173.

    Article  PubMed  PubMed Central  Google Scholar 

  13. DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK . Beta-arrestins and cell signaling. Annu Rev Physiol 2007; 69: 483–510.

    CAS  Article  PubMed  Google Scholar 

  14. Lefkowitz RJ, Shenoy SK . Transduction of receptor signals by beta-arrestins. Science 2005; 308: 512–517.

    CAS  Article  PubMed  Google Scholar 

  15. Valentino RJ, Van Bockstaele E, Bangasser D . Sex-specific cell signaling: the corticotropin-releasing factor receptor model. Trends Pharmacol Sci 2013; 34: 437–444.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Stenzel-Poore MP, Cameron VA, Vaughan J, Sawchenko PE, Vale W . Development of Cushing's syndrome in corticotropin-releasing factor transgenic mice. Endocrinology 1992; 130: 3378–3386.

    CAS  Article  PubMed  Google Scholar 

  17. Dong H, Murphy KM, Meng L, Montalvo-Ortiz J, Zeng Z, Kolber BJ et al. Corticotrophin releasing factor accelerates neuropathology and cognitive decline in a mouse model of Alzheimer's disease. J Alzheimer's Dis 2012; 28: 579–592.

    CAS  Article  Google Scholar 

  18. McNulty DE, Annan RS . Hydrophilic interaction chromatography for fractionation and enrichment of the phosphoproteome. Methods Mol Biol 2009; 527: 93–105, x.

    CAS  Article  PubMed  Google Scholar 

  19. Wojcechowskyj JA, Lee JY, Seeholzer SH, Doms RW . Quantitative phosphoproteomics of CXCL12 (SDF-1) signaling. PLoS One 2011; 6: e24918.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Margolin AA, Ong SE, Schenone M, Gould R, Schreiber SL, Carr SA et al. Empirical Bayes analysis of quantitative proteomics experiments. PLoS One 2009; 4: e7454.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Carroll JC, Iba M, Bangasser DA, Valentino RJ, James MJ, Brunden KR et al. Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy. J Neurosci 2011; 31: 14436–14449.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Augustinack JC, Schneider A, Mandelkow EM, Hyman BT . Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease. Acta Neuropathol 2002; 103: 26–35.

    CAS  Article  PubMed  Google Scholar 

  23. Ma X, Zhao Y, Daaka Y, Nie Z . Acute activation of beta2-adrenergic receptor regulates focal adhesions through betaArrestin2- and p115RhoGEF protein-mediated activation of RhoA. J Biol Chem 2012; 287: 18925–18936.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Vassar R, Citron M . Abeta-generating enzymes: recent advances in beta- and gamma-secretase research. Neuron 2000; 27: 419–422.

    CAS  Article  PubMed  Google Scholar 

  25. Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K . Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimer's Dis 2013; 33 (Suppl 1): S123–S139.

    Google Scholar 

  26. Hruska M, Dalva MB . Ephrin regulation of synapse formation, function and plasticity. Mol Cell Neurosci 2012; 50: 35–44.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Pei JJ, Bjorkdahl C, Zhang H, Zhou X, Winblad B . P70 S6 kinase and tau in Alzheimer's disease. J Alzheimers Dis 2008; 14: 385–392.

    Article  PubMed  Google Scholar 

  28. Sluchanko NN, Gusev NB . Probable participation of 14-3-3 in tau protein oligomerization and aggregation. J Alzheimers Dis 2011; 27: 467–476.

    CAS  Article  PubMed  Google Scholar 

  29. Hruska M, Dalva MB . Ephrin regulation of synapse formation, function and plasticity. Mol Cell Neurosci 2012; 50: 35–44.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Pei JJ, Bjorkdahl C, Zhang H, Zhou X, Winblad B . p70 S6 kinase and tau in Alzheimer's disease. J Alzheimer's Dis 2008; 14: 385–392.

    Article  Google Scholar 

  31. Sluchanko NN, Gusev NB . Probable participation of 14-3-3 in tau protein oligomerization and aggregation. J Alzheimer's Dis 2011; 27: 467–476.

    CAS  Article  Google Scholar 

  32. Hirata-Fukae C, Li HF, Ma L, Hoe HS, Rebeck GW, Aisen PS et al. Levels of soluble and insoluble tau reflect overall status of tau phosphorylation in vivo. Neurosci Lett 2009; 450: 51–55.

    CAS  Article  PubMed  Google Scholar 

  33. Wilson RS, Evans DA, Bienias JL, Mendes de Leon CF, Schneider JA, Bennett DA . Proneness to psychological distress is associated with risk of Alzheimer's disease. Neurology 2003; 61: 1479–1485.

    CAS  Article  PubMed  Google Scholar 

  34. Swanwick GR, Kirby M, Bruce I, Buggy F, Coen RF, Coakley D et al. Hypothalamic-pituitary-adrenal axis dysfunction in Alzheimer's disease: lack of association between longitudinal and cross-sectional findings. Am J Psychiatry 1998; 155: 286–289.

    CAS  Article  PubMed  Google Scholar 

  35. Umegaki H, Ikari H, Nakahata H, Endo H, Suzuki Y, Ogawa O et al. Plasma cortisol levels in elderly female subjects with Alzheimer's disease: a cross-sectional and longitudinal study. Brain Res 2000; 881: 241–243.

    CAS  Article  PubMed  Google Scholar 

  36. Csernansky JG, Dong H, Fagan AM, Wang L, Xiong C, Holtzman DM et al. Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am J Psychiatry 2006; 163: 2164–2169.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Landfield PW, Blalock EM, Chen KC, Porter NM . A new glucocorticoid hypothesis of brain aging: implications for Alzheimer's disease. Curr Alzheimer Res 2007; 4: 205–212.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Rissman RA, Staup MA, Lee AR, Justice NJ, Rice KC, Vale W et al. Corticotropin-releasing factor receptor-dependent effects of repeated stress on tau phosphorylation, solubility, and aggregation. Proc Natl Acad Sci USA 2012; 109: 6277–6282.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Brunden KR, Trojanowski JQ, Lee VM . Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies. Nat Rev Drug Discov 2009; 8: 783–793.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Bramblett GT, Goedert M, Jakes R, Merrick SE, Trojanowski JQ, Lee VM . Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron 1993; 10: 1089–1099.

    CAS  Article  PubMed  Google Scholar 

  41. Aznar S, Knudsen GM . Depression and Alzheimer's disease: is stress the initiating factor in a common neuropathological cascade? J Alzheimers Dis 2011; 23: 177–193.

    Article  PubMed  Google Scholar 

  42. Andersen K, Launer LJ, Dewey ME, Letenneur L, Ott A, Copeland JRM et al. Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. Neurology 1999; 53: 1992–1997.

    CAS  Article  PubMed  Google Scholar 

  43. Fratiglioni L, Small BJ, Winblad B, Bäckman L . The transition from normal functioning to dementia in the ageing population. In: Iqbal K, Sisodia S, Winblad B (eds). Alzheimer’s Disease: Advances in Etiology, Pathogenesis and Therapeutics. Wiley: Chichester, UK, 2001, pp 3–10.

    Google Scholar 

  44. Ruitenberg A, Ott A, van Swieten JC, Hofman A, Breteler MMB . Incidence of dementia: does gender make a difference? Neurobiol Aging 2001; 22: 575–580.

    CAS  Article  PubMed  Google Scholar 

  45. Nunan J, Small DH . Regulation of APP cleavage by alpha-, beta- and gamma-secretases. FEBS Lett 2000; 483: 6–10.

    CAS  Article  PubMed  Google Scholar 

  46. Kang JE, Cirrito JR, Dong H, Csernansky JG, Holtzman DM . Acute stress increases interstitial fluid amyloid-beta via corticotropin-releasing factor and neuronal activity. Proc Natl Acad Sci USA 2007; 104: 10673–10678.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Dong H, Wang S, Zeng Z, Li F, Montalvo-Ortiz J, Tucker C et al. Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-beta and behavior in Tg2576 mice. Psychopharmacology 2014; 231: 4711–4722.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Walter J, Fluhrer R, Hartung B, Willem M, Kaether C, Capell A et al. Phosphorylation regulates intracellular trafficking of beta-secretase. J Biol Chem 2001; 276: 14634–14641.

    CAS  Article  PubMed  Google Scholar 

  49. Park HJ, Ran Y, Jung JI, Holmes O, Price AR, Smithson L et al. The stress response neuropeptide CRF increases amyloid-beta production by regulating gamma-secretase activity. EMBO J 2015; 34: 1674–1686.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Thathiah A, Horre K, Snellinx A, Vandewyer E, Huang Y, Ciesielska M et al. Beta-arrestin 2 regulates Abeta generation and gamma-secretase activity in Alzheimer's disease. Nat Med 2013; 19: 43–49.

    CAS  Article  PubMed  Google Scholar 

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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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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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