Truncation of Tau selectively facilitates its pathological activities.

Neurofibrillary tangles of abnormally hyperphosphorylated Tau are a hallmark of Alzheimer's disease (AD) and related tauopathies. Tau is truncated at multiple sites by various proteases in AD brain. Although many studies have reported the effect of truncation on the aggregation of Tau, these studies mostly employed highly artificial conditions, using heparin sulfate or arachidonic acid to induce aggregation. Here, we report for the first time the pathological activities of various truncations of Tau, including site-specific phosphorylation, self-aggregation, binding to hyperphosphorylated and oligomeric Tau isolated from AD brain tissue (AD O-Tau), and aggregation seeded by AD O-Tau. We found that deletion of the first 150 or 230 amino acids (aa) enhanced Tau's site-specific phosphorylation, self-aggregation, and binding to AD O-Tau and aggregation seeded by AD O-Tau, but deletion of the first 50 aa did not produce a significant effect. Deletion of the last 50 aa was found to modulate Tau's site-specific phosphorylation, promote its self-aggregation, and cause it to be captured by and aggregation seeded by AD O-Tau, whereas deletion of the last 20 aa had no such effects. Among the truncated Taus, Tau151-391 showed the highest pathological activities. AD O-Tau induced aggregation of Tau151-391in vitro and in cultured cells. These findings suggest that the first 150 aa and the last 50 aa protect Tau from pathological characteristics and that their deletions facilitate pathological activities. Thus, inhibition of Tau truncation may represent a potential therapeutic approach to suppress Tau pathology in AD and related tauopathies.