Chronic Corticosterone Exposure Increases Expression and Decreases Deoxyribonucleic Acid Methylation of Fkbp5 in Mice

Lee, Richard S.; Tamashiro, Kellie L.K.; Yang, Xia; Purcell, Ryan H.; Harvey, A. McGehee; Willour, Virginia L.; Huo, Yuqing; Rongione, Michael; Wand, Gary S.; Potash, James B.

doi:10.1210/en.2010-0225

Cited by 242 publications

(216 citation statements)

References 46 publications

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“…Thus, factors that facilitate FKBP51 expression could promote an environment in the aging brain that supports tau pathogenesis. We show that FKBP5 methylation is reduced both with age and in disease, which could be one factor leading to increased FKBP51 expression (54,57,58). FKBP5 methylation and FKBP51 expression appear to be inversely proportional over time.…”

Section: Discussionmentioning

confidence: 75%

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

et al. 2013

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Aggregation of tau protein in the brain is associated with a class of neurodegenerative diseases known as tauopathies. FK506 binding protein 51 kDa (FKBP51, encoded by FKBP5) forms a mature chaperone complex with Hsp90 that prevents tau degradation. In this study, we have shown that tau levels are reduced throughout the brains of Fkbp5 -/-mice. Recombinant FKBP51 and Hsp90 synergized to block tau clearance through the proteasome, resulting in tau oligomerization. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved the species of tau that have been linked to Alzheimer's disease (AD) pathogenesis, blocked amyloid formation, and decreased tangle load in the brain. Alterations in tau turnover and aggregate structure corresponded with enhanced neurotoxicity in mice. In human brains, FKBP51 levels increased relative to age and AD, corresponding with demethylation of the regulatory regions in the FKBP5 gene. We also found that higher FKBP51 levels were associated with AD progression. Our data support a model in which age-associated increases in FKBP51 levels and its interaction with Hsp90 promote neurotoxic tau accumulation. Strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 have the potential to be therapeutically relevant for AD and other tauopathies.

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Section: Discussionmentioning

confidence: 75%

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

et al. 2013

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“…Previous reports from the clinical literature have shown that methylation of the Fkbp5 gene (at the promoter region of exon 1) did not predict treatment response, but decreased in association with recovery (Yehuda et al, 2013). A study using a chronic corticosterone administration paradigm, that had been previously shown to result in a phenotype similar to chronic stress exposure (Gourley et al, 2009), induced an increase in Fkbp5 mRNA expression in the hippocampus, hypothalamus, and blood of mice with a correspondent decrease in DNA methylation at Fkbp5 intron 5 (Lee et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…DNA methylation at functional glucocorticoid response elements in mouse Fkbp5 intron 5 described by Lee et al (2010) was performed based on procedures described by Sabbagh et al (2014), using Varionostic GmbH, Inc (Ulm, Germany, www.varionostic.de). Briefly, 500 ng genomic DNA was bisulfite-converted using the EZ-96 DNA methylation kit (Zymo, Irvine, CA).…”

Section: Dna Methylation Analysesmentioning

confidence: 99%

“…We therefore hypothesized that dexamethasone administration would alter Fkbp5 DNA methylation leading to an alteration of Fkbp5 expression. We investigated DNA methylation in and around a functional GR binding site in intron 5 of Fkbp5 previously shown to be responsive to corticosterone administration (Lee et al, 2010). Sequenom Epityper was performed at six CpG dinucleotides in intron 5 of the mouse Fkbp5 gene in the amygdala of mice treated with dexamethasone and compared with those of vehicle-treated controls at 2 and 6 h after EXT (Figure 3a and b).…”

Section: Changes In Methylation Of Fkbp5 In Imo Mice Following Dexamementioning

confidence: 99%

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Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Sawamura

Klengel

Armario

et al. 2015

Neuropsychopharmacol

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Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shockmediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

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“…The study by Li et al (2015) did not detect a stress-related change in total methylation levels (i.e., 5-mC + 5-hmC), suggesting that the increase in 5-hmC was paralleled by a decrease in 5-mC, which collectively induced the stress-related NR3C1 upregulation. Stress exposure may additionally induce alterations in the epigenetic regulation of FK506 binding protein 5 (FKBP5), a known regulator of GR sensitivity (Binder 2009), as corticosterone administration during adulthood was shown to increase anxiety-like behaviour and elevate mouse hippocampal FKBP5 expression (and thus potentiate GR sensitivity) by decreasing DNA methylation at the Fkbp5 locus (Lee et al 2010). These findings collectively suggest that disrupted negative glucocorticoid feedback, as observed in PTSD, is characterized by elevated hippocampal and PFC GR levels, mediated by epigenetic mechanisms on the DNA and RNA level.…”

Section: Corticosterone Signallingmentioning

confidence: 99%

Epigenetic programming of the neuroendocrine stress response by adult life stress

Dirven

Homberg

Kozicz

et al. 2017

Journal of Molecular Endocrinology

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The hypothalamic-pituitary-adrenal (HPA) axis is critically involved in the neuroendocrine regulation of stress adaptation, and the restoration of homeostasis following stress exposure. Dysregulation of this axis is associated with stress-related pathologies like major depressive disorder, post-traumatic stress disorder, panic disorder and chronic anxiety. It has long been understood that stress during early life can have a significant lasting influence on the development of the neuroendocrine system and its neural regulators, partially by modifying epigenetic regulation of gene expression, with implications for health and well-being in later life. Evidence is accumulating that epigenetic plasticity also extends to adulthood, proposing it as a mechanism by which psychological trauma later in life can long-lastingly affect HPA axis function, brain plasticity, neuronal function and behavioural adaptation to neuropsychological stress. Further corroborating this claim is the phenomenon that these epigenetic changes correlate with the behavioural consequences of trauma exposure. Thereby, epigenetic modifications provide a putative molecular mechanism by which the behavioural phenotype and transcriptional/translational potential of genes involved in HPA axis regulation can change drastically in response to environmental challenges, and appear an important target for treatment of stress-related disorders. However, improved insight is required to increase their therapeutic (drug) potential. Here, we provide an overview of the growing body of literature describing the epigenetic modulation of the (primarily neuroendocrine) stress response as a consequence of adult life stress and interpret the implications for, and the challenges involved in applying this knowledge to, the identification and treatment of stress-related psychiatric disorders.

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Chronic Corticosterone Exposure Increases Expression and Decreases Deoxyribonucleic Acid Methylation of Fkbp5 in Mice

Cited by 242 publications

References 46 publications

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Epigenetic programming of the neuroendocrine stress response by adult life stress

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