| Publication Abstract Display | | Type: Published Abstract | | Title: Immunophilins FKBP4 and FKBP5 as potential state-markers for major depressive disorder in HIV patients. | | Authors: Nguyen T, Tatro E, Kwok J, Bousman C, Soontornniyomkij, Grant I, Achim C, Everall I | | Year: 2009 | | Publication: Society for Neuroscience, Chicago, Illinois, October 17-21 | | Volume: Issue: Pages: | | Abstract:Immunophilins FKBP4 and FKBP5 are shown to modulate glucocorticoid receptor (GR) signaling in neurons and play a role in HPA axis function of the CNS. Polymorphisms in the FKBP5 gene were shown to associate with HPA axis - related disorders such as major depressive disorder (MDD). Dysregulated HPA axis is thought to have negative CNS effects leading such disorders and we hypothesize that FKBP4 and -5 play a role in MDD in HIV-infected patients. FKBP4 and FKBP5 expression were increased in frontal cortex of HIV-infected subjects. In vitro, we sought to determine whether neuronal FKBP expression increased on exposure to HIV. In vivo, we sought to determine whether FKBP expression was altered in MDD in HIV patients in a panel enrolled in a study on CNS HAART Effects Research (CHARTER) in which PBMCs were obtained during and without MDD episode.
Methods
Primary neuronal cultures were exposed to 500nM cortisol with/out 6000pg/mL HIV macrophage-conditioned media for 30, 60min, and 12hr. FKBP4 and FKBP5 expression were determined using TaqMan qPCR. A sample of 54 patients from CHARTER was supplied with paired Depressed/Remissive clinical blood samples and neuropsych data. PBMC RNA was additionally assessed for SNP rs3800373 in FKBP5 3 UTR. ANOVAs comparing expression at 2 clinical timepoints with effects sizes (Cohen`s D) were performed.
Results
We found in vitro increase in both FKBP4 and FKBP5, with FKBP4 increasing earlier than FKBP5. FKBP5 increased transiently in response to cortisol, while FKBP4 did not change. In Cohort 1, the Remissive to Depressed group, FKBP5 expression increased during a MDD episode. Conversely, in Cohort 2, the Depressed to Remissive group, FKBP5 was lower during a MDD episode. FKBP4 expression correlated to Beck`s Depressive Index score (BDI) in non-depressed state and the TT genotype in Cohort 2 significantly correlated to improvement in BDI.
Discussion
The kinetics of neuronal FKBP response to HIV indicate that FKBP4 expression increases early, which may increase GR signaling regardless of hormone concentration, having neurotoxic effect. FKBP5, the GR antagonist, expression increases at a later time, potentially as a balancing mechanism. In line with the Glucocorticoid Cascade Hypothesis and neuronal FKBP-GR mechanistics, we found imbalance in FKBP4/5 expression in the depressed state. Both Cohorts had the same FKBP5 expression in the non-depressed remissive state. However, in Cohort 1, FKBP5 expression increased after developing depression, and in Cohort 2, FKBP5 expression increased after therapy. The SNP may be a target for pharmacogenomic study. The balance of FKBP4/5 expression and relation to MDD seems to be complex and affected by HIV |
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