Age-associated epigenetic upregulation of the FKBP5 gene selectively impairs stress resiliency.

Jonathan J Sabbagh,John C O'Leary,Chad A Dickey,Sarah N Fontaine,Torsten Klengel,Laura J Blair,Elisabeth B Binder,Bryce A Nordhues,Takeo Yoshikawa

doi:10.1371/journal.pone.0107241

Abstract

Single nucleotide polymorphisms (SNPs) in the FK506 binding protein 5 (FKBP5) gene combine with traumatic events to increase risk for post-traumatic stress and major depressive disorders (PTSD and MDD). These SNPs increase FKBP51 protein expression through a mechanism involving demethylation of the gene and altered glucocorticoid signaling. Aged animals also display elevated FKBP51 levels, which contribute to impaired resiliency to depressive-like behaviors through impaired glucocorticoid signaling, a phenotype that is abrogated in FKBP5−/− mice. But the age of onset and progressive stability of these phenotypes remain unknown. Moreover, it is unclear how FKBP5 deletion affects other glucocorticoid-dependent processes or if age-associated increases in FKBP51 expression are mediated through a similar epigenetic process caused by SNPs in the FKBP5 gene. Here, we show that FKBP51-mediated impairment in stress resiliency and glucocorticoid signaling occurs by 10 months of age and this increased over their lifespan. Surprisingly, despite these progressive changes in glucocorticoid responsiveness, FKBP5−/− mice displayed normal longevity, glucose tolerance, blood composition and cytokine profiles across lifespan, phenotypes normally associated with glucocorticoid signaling. We also found that methylation of Fkbp5 decreased with age in mice, a process that likely explains the age-associated increases in FKBP51 levels. Thus, epigenetic upregulation of FKBP51 with age can selectively impair psychological stress-resiliency, but does not affect other glucocorticoid-mediated physiological processes. This makes FKBP51 a unique and attractive therapeutic target to treat PTSD and MDD. In addition, aged wild-type mice may be a useful model for investigating the mechanisms of FKBP5 SNPs associated with these disorders.

Highlights

Late-life depression (LLD) is a debilitating disorder that can accelerate aging and mortality [1,2,3]
The FK506 binding protein 5 (FKBP5) gene is associated with depression [10], post-traumatic stress disorder (PTSD) [9], anxiety [11,26] and Alzheimer’s disease (AD) [7,8], but little is known about its role in aging
We have shown progressive Fkbp5 demethylation occurs with age in wild-type mice, elucidating a mechanism by which FK506 binding protein 51 (FKBP51) levels increase throughout life

Summary

Introduction

Late-life depression (LLD) is a debilitating disorder that can accelerate aging and mortality [1,2,3]. FKBP51 has an inhibitory effect on GR, decreasing the affinity of cortisol or corticosterone (CORT) for GR [14] and impairing GR translocation [15]. This inhibition delays negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, prolongs the stress response and leads to elevated circulating CORT levels and glucocorticoid resistance. Previous work from our laboratory and others has shown that ablation of FKBP5 in mice leads to an age-dependent anti-depressive phenotype, more robust coping behavior following stress, and reduced stressinduced circulating CORT levels without altering cognitive function [5,6,16]. Attenuating the effect of FKBP51 on HPA axis dysregulation is an attractive therapeutic strategy for depression, especially in aged individuals

Methods

Results

Conclusion