FKBP52 overexpression accelerates hippocampal-dependent memory impairments in a tau transgenic mouse model.

Abnormal accumulation of hyperphosphorylated tau induces pathogenesis in neurodegenerative diseases, like Alzheimer's disease. Molecular chaperones with peptidyl-prolyl cis/trans isomerase (PPIase) activity are known to regulate these processes. Previously, in vitro studies have shown that the 52 kDa FK506-binding protein (FKBP52) interacts with tau inducing its oligomerization and fibril formation to promote toxicity. Thus, we hypothesized that increased expression of FKBP52 in the brains of tau transgenic mice would alter tau phosphorylation and neurofibrillary tangle formation ultimately leading to memory impairments. To test this, tau transgenic (rTg4510) and wild-type mice received bilateral hippocampal injections of virus overexpressing FKBP52 or GFP control. We examined hippocampal-dependent memory, synaptic plasticity, tau phosphorylation status, and neuronal health. This work revealed that rTg4510 mice overexpressing FKBP52 had impaired spatial learning, accompanied by long-term potentiation deficits and hippocampal neuronal loss, which was associated with a modest increase in total caspase 12. Together with previous studies, our findings suggest that FKBP52 may sensitize neurons to tau-mediated dysfunction via activation of a caspase-dependent pathway, contributing to memory and learning impairments.

A Human Microbiota-Associated Murine Model for Assessing the Impact of the Vaginal Microbiota on Pregnancy Outcomes.

Disease states are often linked to large scale changes in microbial community structure that obscure the contributions of individual microbes to disease. Establishing a mechanistic understanding of how microbial community structure contribute to certain diseases, however, remains elusive thereby limiting our ability to develop successful microbiome-based therapeutics. Human microbiota-associated (HMA) mice have emerged as a powerful approach for directly testing the influence of microbial communities on host health and disease, with the transfer of disease phenotypes from humans to germ-free recipient mice widely reported. We developed a HMA mouse model of the human vaginal microbiota to interrogate the effects of Bacterial Vaginosis (BV) on pregnancy outcomes. We collected vaginal swabs from 19 pregnant African American women with and without BV (diagnosed per Nugent score) to colonize female germ-free mice and measure its impact on birth outcomes. There was considerable variability in the microbes that colonized each mouse, with no association to the BV status of the microbiota donor. Although some of the women in the study had adverse birth outcomes, the vaginal microbiota was not predictive of adverse birth outcomes in mice. However, elevated levels of pro-inflammatory cytokines in the uterus of HMA mice were detected during pregnancy. Together, these data outline the potential uses and limitations of HMA mice to elucidate the influence of the vaginal microbiota on health and disease.

FKBP5 and early life stress affect the hippocampus by an age-dependent mechanism.

Early life stress (ELS) adversely affects the brain and is commonly associated with the etiology of mental health disorders, like depression. In addition to the mood-related symptoms, patients with depression show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increased peripheral inflammation, and structural brain alterations. Although the underlying causes are unknown, polymorphisms in the FK506-binding protein 5 (FKBP5) gene, a regulator of glucocorticoid receptor (GR) activity, interact with childhood adversities to increase vulnerability to depressive disorders. We hypothesized that high FKBP5 protein levels combined with early life stress (ELS) would alter the HPA axis and brain, promoting depressive-like behaviors. To test this, we exposed males and females of a mouse model overexpressing FKBP5 in the brain (rTgFKBP5 mice), or littermate controls, to maternal separation for 14 days after birth. Then, we evaluated neuroendocrine, behavioral, and brain changes in young adult and aged mice. We observed lower basal corticosterone (CORT) levels in rTgFKBP5 mice, which was exacerbated in females. Aged, but not young, rTgFKBP5 mice showed increased depressive-like behaviors. Moreover, FKBP5 overexpression reduced hippocampal neuron density in aged mice, while promoting markers of microglia expression, but these effects were reversed by ELS. Together, these results demonstrate that high FKBP5 affects basal CORT levels, depressive-like symptoms, and numbers of neurons and microglia in the hippocampus in an age-dependent manner.

Early Life Stress and High FKBP5 Interact to Increase Anxiety-Like Symptoms through Altered AKT Signaling in the Dorsal Hippocampus.

Clinical studies show a significant association of childhood adversities and FK506-binding protein 5 (FKBP5) polymorphisms on increasing the susceptibility for neuropsychiatric disorders. However, the mechanisms by which early life stress (ELS) influences FKBP5 actions have not been fully elucidated. We hypothesized that interactions between ELS and high FKBP5 induce phenotypic changes that correspond to underlying molecular changes in the brain. To test this, we exposed newborn mice overexpressing human FKBP5 in the forebrain, rTgFKBP5, to ELS using a maternal separation. Two months after ELS, we observed that ELS increased anxiety levels, specifically in mice overexpressing FKBP5, an effect that was more pronounced in females. Biochemically, Protein kinase B (AKT) phosphorylation was reduced in the dorsal hippocampus in rTgFKBP5 mice, which demonstrates that significant molecular changes occur as a result of ELS when FKBP5 levels are altered. Taken together, our results have a significant impact on our understanding mechanisms underlying the gene x environment interaction showing that anxiety and AKT signaling in the hippocampus were affected by the combination of ELS and FKBP5. An increased knowledge of the molecular mechanisms underlying these interactions may help determine if FKBP5 could be an effective target for the treatment of anxiety and other mood-related illnesses.