C-Terminally Truncated Forms of Tau, But Not Full-Length Tau or Its C-Terminal Fragments, Are Released from Neurons Independently of Cell Death

Significance Statement: Recent studies suggest that the transfer of tau between neurons underlies the characteristic spatiotemporal progression of neurofibrillary pathology. We searched for tau in the conditioned medium of N2a cells, induced pluripotent stem cell-derived human cortical neurons, and primary rat cortical neurons and analyzed the material present using four different tau ELISAs. We demonstrate that the majority of tau released from healthy neurons is C-terminally truncated and lacks the microtubule-binding region (MTBR) thought necessary for self-aggregation. A small amount of MTBR-containing tau is present outside of cells, but this appears to be solely due to cell death. Therefore, if propagation of tau aggregation is mediated by extracellular tau, our findings suggest that neuronal compromise is required to facilitate this process.