FKBP51 mediates mitochondrial function via NF-κB pathway during sleep fragmentation-induced cognitive impairment

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Sleep disruption is linked to neuroinflammation and cognitive deficits.
• FKBP51 (FK506-binding protein 51) is implicated in stress disorders, but its role in sleep regulation is unknown.

Purpose of the Study:

• To investigate the role of FKBP51 in cognitive deficits and neuroinflammation induced by sleep fragmentation (SF).
• To explore FKBP51 as a therapeutic target for SF-related impairments.

Main Methods:

• Mice were subjected to sleep fragmentation (SF).
• Transcriptomic and proteomic profiling were used to analyze hippocampal gene expression.
• FKBP51 knockout (Fkbp5^-/-) and knockdown models were employed.
• In vitro assays assessed mitochondrial function and apoptosis.
• SAFit2, an FKBP51 inhibitor, was tested in SF-exposed mice.

Main Results:

• SF increased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and upregulated Fkbp5 expression in the hippocampus.
• Fkbp5 knockout mice showed protection against SF-induced NF-κB activation, mitochondrial dysfunction, apoptosis, and cognitive deficits.
• SAFit2 treatment reversed SF-induced inflammation, mitochondrial dysfunction, and cognitive impairment.

Conclusions:

• FKBP51 plays a critical role in mediating SF-induced neuroinflammation and cognitive deficits.
• Downregulation of FKBP51 mitigates SF effects by inhibiting NF-κB signaling and preserving mitochondrial function.
• Targeting FKBP51 with inhibitors like SAFit2 is a promising therapeutic approach for sleep disruption-related disorders.