Extracellular vesicles isolated from brains of rTg4510 mice seed tau aggregation in a threshold-dependent manner

Juan Carlos Polanco1, Benjamin James Scicluna2, Andrew Francis Hill3 and Jürgen Götz1*doi: 10.1074/jbc.M115.709485 March 30, 2016

The microtubule-associated protein tau has a critical role in Alzheimer’s disease and related tauopathies. There is accumulating evidence that tau aggregates spread and replicate in a prion-like manner, with the uptake of pathological tau seeds causing misfolding and aggregation of monomeric tau in recipient cells. Here, we focused on small extracellular vesicles enriched for exosomes, that were isolated from brains of tau transgenic rTg4510 and control mice. We found that these extracellular vesicles contained tau, albeit levels were significantly higher in the transgenic mice that have a pronounced tau pathology. Tau in the vesicles was differentially phosphorylated, although to a lower degree than in the brain cells from which they were derived. Several phospho-epitopes (AT8, AT100 and AT180) thought to be critical for tau pathology were undetected in extracellular vesicles. Despite of this, when assayed with FRET tau biosensor cells, extracellular vesicles derived from transgenic mice were capable of seeding tau aggregation in a threshold-dependent manner. We also observed that the dye used to label extracellular vesicle membranes was still present during nucleation and formation of tau inclusions suggesting either a role for membranes in the seeding or that are in the process of degradation. Together, we clearly demonstrate that extracellular vesicles can transmit tau pathology. This indicates a role for extracellular vesicles in the transmission and spreading of tau pathology. The characteristics of tau in the extracellular vesicles and the seeding threshold we had identified may explain why tau pathology develops very slowly in neurodegenerative diseases such as Alzheimer’s disease.
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