SUMMARY
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 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 and notably, only a small fraction of Tau, separated by ultracentrifugation, is seeding competent. These results indicate that only a subset of Tau accounts for ISF seeding competence and have the potential to contribute to the propagation of Tau pathology.
Highlights
✓ In transgenic mice, interstitial fluid comprises several Tau fragments spanning the entire Tau sequence.
✓ Interstitial fluid Tau concentration decreases with Tauopathy progression, while phosphorylation increases.
✓ Only interstitial fluid from mice with established Tauopathy is seeding competent in vitro.
✓ Interstitial fluid seeding competence is driven by less soluble, aggregated and phosphorylated Tau species.
In Brief Barini et al. show that in the brain interstitial fluid of Tau transgenic mice, truncated Tau decreases, while its phosphorylation increases during the progression of pathology. A subset of less soluble, aggregated and phosphorylated ISF Tau induces Tau aggregation in cells.
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
