First-in-Rat Study of Human Alzheimer’s Disease Tau Propagation

Tomas Smolek, Santosh Jadhav, Veronika Brezovakova, Veronika Cubinkova, Bernadeta Valachova, Petr Novak, Norbert Zilka

One of the key features of misfolded tau in human neurodegenerative disorders is its propagation from one brain area into many others. In the last decade, in vivo tau spreading has been replicated in several mouse transgenic models expressing mutated human tau as well as in normal non-transgenic mice. In this study, we demonstrate for the first time that insoluble tau isolated from human AD brain induces full-blown neurofibrillary pathology in a sporadic rat model of tauopathy expressing non-mutated truncated tau protein. By using specific monoclonal antibodies, we were able to monitor the spreading of tau isolated from human brain directly in the rat hippocampus. We found that exogenous human AD tau was able to spread from the area of injection and induce tau pathology. Interestingly, solubilisation of insoluble AD tau completely abolished the capability of tau protein to induce and spread of neurofibrillary pathology in the rat brain. Our results show that exogenous tau is able to induce and drive neurofibrillary pathology in rat model for human tauopathy in a similar way as it was described in various mouse transgenic models. Rat tau spreading model has many advantages over mouse and other organisms including size and complexity, and thus is highly suitable for identification of pathogenic mechanism of tau spreading.