FK506-binding Protein 51 Knockout Mice Research Articles

The novel FKBP51‐Hsp90 interaction inhibitor attenuates high‐fat diet induced cognitive impairment

AbstractBackgroundObesity increases the risk of several chronic diseases, such as type 2 diabetes mellitus, insulin resistance, and Alzheimer disease. As one of the co‐chaperones of heat shock protein 90 (Hsp90), FK506‐binding protein 51 (FKBP51) is an important regulator of metabolic and cognitive dysfunction. FKBP51 knockout mice are resistant to diet‐induced obesity, exhibit elevated glucose and insulin tolerance and have less endogenous tau. FKBP51 overexpression preserves tau and impairs spatial reversal learning and memory. Our group has identified a new family of FKBP51 inhibitors that can disrupt FKBP51‐Hsp90 interactions. Previous study has shown that our inhibitors can dose‐dependently reduce lipid accumulation in adipocytes differentiated from primary human mesenchymal stem cells and stimulate neurite outgrowth in differentiated neuroblastoma SH‐SY5Y cells. This study aims to investigate the potential roles of our inhibitors on metabolic and cognitive dysfunction in vivo.MethodsPharmacokinetic studies have been performed at first. Plasma and brain samples were collected and analyzed by liquid chromatography‐mass spectrometry. Male C57BL/6J mice were fed either the control or high‐fat diet (HFD) for 4 weeks and then treated with vehicle or inhibitor E8 (20 mg/kg, s.c.) and their respective diets for another 4 weeks. Behaviors, body composition measuremnets by EchoMRI, fasting glucose/insulin detections and glucose/insulin tolerance tests were performed during the last week. Hippocampus was collected for western blot, RNA sequencing and quantitative real‐time PCR analysis.ResultsAfter subcutaneous injection, E8 can be quickly absorbed into the blood and penetrate the blood‐brain barrier. In HFD model, E8 can attenuate the impairment of locomotor activity and short‐term memory. But it could neither reduce body weight gain nor improve insulin sensitivity and glucose/insulin tolerance. In the hippocampus, E8 reduces the elevated p‐tau (Ser214)/tau levels induced by HFD but does not show any effects on insulin signaling. It suggests that E8 reverses the behavioral impairments independently of metabolic regulation in vivo. The underlying mechanisms were further investigated by RNA sequencing and quantitative real‐time PCR analysis.ConclusionWe showed that inhibiting FKBP51‐Hsp90 interactions with small molecules provides novel therapeutic targets on cognitive dysfunction in obesity.

The Impact of FKBP5 Deficiency in Glucocorticoid Receptor Mediated Regulation of Synaptic Transmission in the Medial Prefrontal Cortex

Exposure to stress activates glucocorticoid receptors in the brain and facilitates the onset of multitude psychiatric disorders. It has been shown that FK506 binding protein 51 (FKBP5) expression increases during glucocorticoid receptor (GR) activation in various brain regions including the medial prefrontal cortex (mPFC). FKBP5 knockout (KO) mice are reported to be resilient to stress, however, it remains uninvestigated whether FKBP5 loss affects neurotransmission and if so, what the functional consequences are. Here, we examined the impact of FKBP5 deletion in synaptic transmission of the mPFC. We found that GR activation significantly decreased excitatory neurotransmission in the mPFC, which was completely abolished upon FKBP5 deletion, in consistent with behavioral resilience observed in FKBP5 KO mice. Even though FKBP5 loss has minimal impact on neural excitability, we found that FKBP5 deletion distorts the excitatory/inhibitory balance in the mPFC. Our study suggests that FKBP5 deficiency leads to the mPFC insensitive to GR activation and provides a neurophysiological explanation for how FKBP5 deficiency may mediate stress resilience.

Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy.

FKBP51 (FK506-binding protein 51) is a known co-chaperone and regulator of the glucocorticoid receptor (GR), which usually attenuates its activity. FKBP51 is one of the major GR target genes in skin, but its role in clinical effects of glucocorticoids is not known. Here, we used FKBP51 knockout (KO) mice to determine FKBP51's role in the major adverse effect of topical glucocorticoids, skin atrophy. Unexpectedly, we found that all skin compartments (epidermis, dermis, dermal adipose and CD34+ stem cells) in FKBP51 KO animals were much more resistant to glucocorticoid-induced hypoplasia. Furthermore, despite the absence of inhibitory FKBP51, the basal level of expression and glucocorticoid activation of GR target genes were not increased in FKBP51 KO skin or CRISPR/Cas9-edited FKBP51 KO HaCaT human keratinocytes. FKBP51 is known to negatively regulate Akt and mTOR. We found a significant increase in AktSer473 and mTORSer2448 phosphorylation and downstream pro-growth signaling in FKBP51-deficient keratinocytes in vivo and in vitro. As Akt/mTOR-GR crosstalk is usually negative in skin, our results suggest that Akt/mTOR activation could be responsible for the lack of increased GR function and resistance of FKBP51 KO mice to the steroid-induced skin atrophy.

The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling.

Polymorphisms in FKBP51 are associated with stress-related psychiatric disorders and influence the severity of pain symptoms experienced after trauma. We report that FKBP51 (FK506 binding protein 51) is crucial for the full development and maintenance of long-term pain states. Indeed, FKBP51 knockout mice, as well as mice in which silencing of FKBP51 is restricted to the spinal cord, showed reduced hypersensitivity in several persistent pain models in rodents. FKBP51 deletion did not compromise the detection of acute painful stimuli, a critical protective mechanism. Moreover, the intrathecal administration of the specific FKBP51 inhibitor SAFit2 reduced the severity of an established pain state, confirming the crucial role of spinal FKBP51 in nociceptive processing. Finally, glucocorticoid signaling, which is known to modulate persistent pain states in rodents, was impaired in FKBP51 knockout mice. This finding suggested that FKBP51 regulates chronic pain by modulation of glucocorticoid signaling. Thus, FKBP51 is a central mediator of chronic pain, likely in humans as well as rodents, and is a new pharmacologically tractable target for the treatment of long-term pain states.