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Zusammenfassung:
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 2/2 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 2/2 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.
