Refining a Mouse Model of Progressive Supranuclear Palsy Through Inoculation of Human Post-Mortem Brain-Derived Tau

Objective A major obstacle to developing effective therapies for Progressive Supranuclear Palsy (PSP), a uniformly fatal 4R tauopathy, is the absence of an animal model that faithfully reproduces the anatomical, cytopathological, and spatiotemporal progression of disease. Inoculation-based models, using human postmortem brain material bearing disease-specific proteopathic tau seeds, hold great translational potential for modeling tauopathies. Here we conducted key studies towards the development of an inoculation-based PSP model, using human postmortem brain to target three subcortical nuclei impacted in early disease. Results We evaluated the impact of five different PSP brain extracts on the extent and distribution of tau pathology following inoculation into 6hTau transgenic mice expressing all six isoforms of human tau. Our findings demonstrate that 2% sarkosyl-insoluble tau successfully recapitulates core cytopathological features of PSP when introduced into disease-relevant nuclei. However, we also identify a major limitation in the restricted yield of 2% sarkosyl-insoluble tau, which significantly impedes the scalability and reproducibility of this approach. We conclude that further progress will likely require alternative strategies to generate a stable and scalable source of tau proteopathic seeds, to support a robust and reproducible inoculation-based mouse model of PSP.