FKBP51 inhibition by SAFit2 modulates tau pathology and cognitive deficits in PS19 mice

The accumulation of pathogenic tau protein is linked to cognitive decline and neuronal loss in Alzheimer's disease (AD), with tau oligomers identified as particularly neurotoxic. The 51 kDa FK506-binding protein (FKBP51) stabilizes these toxic tau oligomers and has been identified as a risk factor for several neurodegenerative diseases. FKBP51 levels increase with age and are especially high in AD brains, suggesting its involvement in disease progression. The development of the selective FKBP51 inhibitor, SAFit2, which can cross the blood-brain barrier, has shown promise in reducing stress hormones, improving stress responses, and mitigating protein-related pathologies in other neurodegenerative models. However, the effects of SAFit2 on tauopathies, such as those seen in AD, have not yet been investigated. Here, the effects of the FKBP51-selective inhibitor, SAFit2, were evaluated in PS19 tau transgenic mice. Mice received a 28-day regimen of SAFit2, followed by comprehensive behavioral, neuropathological, and proteomic analyses. SAFit2 demonstrated effective brain penetrance, with sex-dependent pharmacokinetics. Treatment slowed cognitive decline and depressive-like behavior, with pronounced benefits in male PS19 mice, including improved spatial memory and reduced tau oligomer burden. In females, SAFit2 promoted clearance of AT8-positive tau multimers with some benefit to recognition memory. Proteomic profiling revealed distinct molecular signatures underlying these sex-specific responses: males exhibited upregulation of RNA processing and ribosomal proteins, while females showed restoration of calcium signaling and synaptic drivers. Notably, behavioral recovery occurred independently of widespread neuroinflammation reversal. These findings provide the first in vivo evidence that FKBP51 inhibition by SAFit2 induces sex-specific remodeling of the brain proteome. This study also provides further evidence for the therapeutic benefits of targeting FKBP51 for tauopathies.