P1‐025: exosomes containing specific tau oligomer formations accelerate pathological tau phosphorylation in c57bl/6 mice

Increasing evidence suggests that tau aggregates spread and replicate via cell-to-cell transmission, with the uptake of pathological tau causing misfolded aggregations of monomeric tau in recipient cells. A single intracerebral inoculation of extracellular vesicles containing tau into murine brains was shown to induce tau phosphorylation and soluble tau oligomer formation. Thus, we hypothesize that tau-containing exosomes derived from Alzheimer's affected human brains can serve as a seed for the spread of tauopathy in recipient animal brains. Exosome-enriched fractions were isolated from unfixed frozen human brain samples from Alzheimer's disease (AD) and control (CTRL) cases, as well as from tau knockout (TKO) mouse brains. Tau oligomer epitopes were determined by dot blot using antibodies against T22, T18, TOMA1, TOMA2, TOMA3 and TOMA4 for all of the exosome fractions that were used as injectates. Two-month old C57BL/6 mice were inoculated with human brain exosomes containing tau, TKO exosomes, or saline, into the right dorsal hippocampus. After injection, the brains were incubated for 18 weeks. The brains were then subjected to immunohistochemistry for phosphorylated-tau (p-tau) epitopes. Each of the human-derived exosome samples has its own unique fingerprint of tau oligomer expression by dot blot. Surprisingly, mice that were injected with one of the AD and with one of the CTRL exosome samples showed remarkable AT8-immunoreactivity in the hilus and subgranular zone regions of the hippocampus, while this was absent in the 9 other injectate groups including TKO-injected mice. Interestingly, one of these two positive exosome samples was only positive for TOMA2, while the other was positive for T22, T18 and TOMA3. Alzheimer's brain derived tau-exosomes accelerate pathological tau phosphorylation in relation to the specific type of tau oligomer(s) included within the exosomes.