Tau in the brain interstitial fluid is fragmented and seeding-competent

In Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that in Tau transgenic mice, human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells. Notably, immunodepletion of ISF phosphorylated Tau, but not Tau fragments, significantly reduces its ability to seed Tau aggregation and only a fraction of Tau, separated by ultracentrifugation, is seeding competent. These results indicate that ISF seeding competence is driven by a small subset of Tau, which potentially contribute to the propagation of Tau pathology. Highlights ![Figure][1] ### Competing Interest Statement The design, study conduct and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 116060 (IMPRiND). This Joint Undertaking receives support from the European Unions Horizon 2020 research and innovation programme and EFPIA. This work is supported by the Swiss State Secretariat for Education, Research and Innovation (SERI) under contract number 17.00038. The opinions expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies. * aCSF : artificial cerebrospinal fluid AD : Alzheimer disease CBD : corticobasal degeneration cOFM : cerebral open flow microperfusion FTD : frontotemporal dementia hTau : human Tau ISF : interstitial fluid IP : immunoprecipitation mTau : mouse Tau PSP : progressive parasupranuclear palsy TauKOTau : knockout mouse line [1]: pending:yes