Truncation of Tau selectively facilitates its pathological activities

Abstract

Neurofibrillary tangles of abnormally hyperphosphorylated tau is a hallmark of Alzheimer’s disease (AD) and related tauopathies. Tau is truncated at multiple sites by various proteases in AD brain. While 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 (a.a.) enhanced tau’s site-specific phosphorylation, self-aggregation, and its binding to AD O-tau, and aggregation seeded by AD O-tau, but deletion of the first 50 a.a. did not produce a significant effect. Deletion of the last 50 a.a. 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 a.a. had no such effects. Among the truncated taus, Tau151-391 showed the highest pathological activities. AD O-tau induced aggregation of Tau151-391 in vitro and in cultured cells. These findings suggest that the first 150 a.a and the last 50 a.a. 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.

Tau in Alzheimer’s Disease: Pathological Alterations and an Attractive Therapeutic Target

“…We observed that deletion of the first 150 or 230 residues of the tau protein increased its self-aggregation, site-specific phosphorylation, and binding to and aggregation seeded by AD O-tau, while the first 50 residues deletion did not have those effects [70] . Deletion of the last 50 residues regulated the tau site-specific phosphorylation and promoted tau self-aggregation, which could be seized and seeded to aggregation by AD O-tau, while the last 20 residues deletion did not show significant effects [70] . Among all the truncated forms, Tau 151-391 was the most pathologically active.…”

“…Truncated tau is more likely to aggregate than full-length tau [62,68,69] . We recently reported that several tau truncations modulate specific sites of phosphorylation, increase tau selfaggregation, and promote the binding to oligomeric tau from AD brain (AD O-tau) and aggregation seeded by AD O-tau [70] . Among all the truncated forms, Tau151-391 causes the most serious pathological disorders and the most potent aggregation effects templated by AD O-tau in cultured cells in vitro [70] .…”

“…Tau is truncated at several sites by different proteases [58,103] and the acidic terminal interacts with MTBRs preventing tau aggregation [104] . We recently constructed 11 truncations from both the C-and N-terminal portions of the tau protein according to the reported truncation sites, and then compared the pathological activities of all the truncated forms [70] . We observed that deletion of the first 150 or 230 residues of the tau protein increased its self-aggregation, site-specific phosphorylation, and binding to and aggregation seeded by AD O-tau, while the first 50 residues deletion did not have those effects [70] .…”

“…We recently constructed 11 truncations from both the C-and N-terminal portions of the tau protein according to the reported truncation sites, and then compared the pathological activities of all the truncated forms [70] . We observed that deletion of the first 150 or 230 residues of the tau protein increased its self-aggregation, site-specific phosphorylation, and binding to and aggregation seeded by AD O-tau, while the first 50 residues deletion did not have those effects [70] . Deletion of the last 50 residues regulated the tau site-specific phosphorylation and promoted tau self-aggregation, which could be seized and seeded to aggregation by AD O-tau, while the last 20 residues deletion did not show significant effects [70] .…”

“…AD O-tau induced Tau151-391 aggregation in cultured cells and in vitro. The deletion of the first 150 and the last 50 residues protected tau from pathological features and facilitated the tau pathological activities [70] . Thus, suppressing tau truncation can be a possible treatment method to inhibit tau pathology in AD and related tauopathies [70] .…”