Increased cortical expression of FK506 binding protein-51 in HIV-associated neurocognitive disorders

Abstract

FK506 binding protein (FKBP)-51 and FKBP52 act as molecular chaperones to control glucocorticoid receptor (GR) sensitivity. Dysregulation of proteins involved in GR-mediated signaling can lead to maladaptive stress response and aging-related cognitive decline. As HIV infection is related to chronic stress, we hypothesized that altered cortical expression of these proteins was associated with HIV-associated neurocognitive disorders (HAND). We used quantitative immunohistochemistry to assess expression levels of these proteins in the mid-frontal gyrus of 55 HIV-infected subjects free of cerebral opportunistic diseases compared to 20 age-matched non-HIV controls. The immunoreactivity normalized to the neuroanatomic area measured (IRn) for FKBP51 was increased in HIV subjects both in the cortex and subcortical white matter (p<0.0001, U test), while no significant alterations were observed for GR or FKBP52. Notably, the cortical FKBP51 IRn was higher in HAND subjects than in cognitively normal HIV subjects (p=0.02, U test). There was also a trend for increasing cortical FKBP51 IRn with the increasing severity of HAND (p=0.08, Kruskal-Wallis test). No significant changes in FKBP51 IRn were found with respect to hepatitis C virus infection, lifetime methamphetamine use, or antiretroviral treatment in HIV subjects. In conclusion, the increased cortical expression of FKBP51 (an inhibitor for GR activity) might represent negative feedback in an attempt to reduce GR sensitivity in the setting of chronic stress-induced elevation of GR-mediated signaling inherent in HIV infection. The further increased FKBP51 expression might lead to maladaptive stress response and HAND.

Cerebral β-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE ε4 carriers

“…The sections were incubated with 90% formic acid (5 min for Aβ staining) or 10 mM sodium citrate/0.05% Tween 20 buffer (pH 6) in 121°C autoclave (20 min for p-Tau staining). Immunohistochemical signals were developed using species-appropriate ImmPRESS ™ anti-IgG (peroxidase) polymer detection kits (Vector Laboratories, Burlingame, CA, USA) and diaminobenzidine (ImmPACT ™ DAB peroxidase substrate, Vector Laboratories), as previously described [31]. The sections were counterstained with hematoxylin.…”

HIV and symptoms of depression are independently associated with impaired glucocorticoid signaling

“…Importantly, expression of FKBP5 and its genetic variations have been linked to a number of psychiatric conditions involving HPA axis dysfunction including depression (Menke et al 2013), post-traumatic stress disorder (Klengel et al 2013), and chronic stress (Hartmann et al 2012). In addition to the established influence of FKBP5 on the GR, FKBP5 has been shown to play a role in HIV-associated cognitive deficits in PLWH (Soontornniyomkij et al 2012, Tatro et al 2009).…”

Regulation of the glucocorticoid response to stress‐related disorders by the Hsp90‐binding immunophilin FKBP51

“…2009a). More recently, a study showed increased cortical expression of FKBP51 in the mid‐frontal gyrus of 55 HIV‐infected subjects free of cerebral opportunistic diseases whereas no significant alterations were observed for GR or FKBP52 (Soontornniyomkij et al. 2012), which would represent the negative feedback to reduce GR sensitivity in the setting of chronic stress‐induced elevation of GR‐mediated signaling inherent in HIV infection and could be related to maladaptive stress response and HIV‐associated neurocognitive disorders.…”