Phosphorylation of Truncated Tau Promotes Abnormal Native Tau Pathology and Neurodegeneration

Abnormal post-translational modifications of tau play important roles in mediating neurodegeneration in tauopathies including Alzheimer’s disease. Both phosphorylation and truncation are implicated in the pathogenesis of tauopathies. However, whether phosphorylation aggravates truncated tau-induced pathology and neurodegeneration remains elusive. Here, we construct different tau fragments cleaved by delta secretase, with either phosphorylation or non-phosphorylation mimic mutations, and evaluate the contributions of phosphorylation to truncated tau-induced pathological and behavior alterations in vitro and in vivo. Our results show that the self-aggregation of phospho-truncated tau is significantly influenced by the domain it contains. N-terminal inhibits, proline-rich domain promotes and C-terminus has no impact on phospho-truncated tau aggregation. Phosphorylation of truncated tau1-368, which contains microtubule binding repeat domain and proline rich domain, induces endogenous tau phosphorylation and aggregation. In vivo, phospho-tau1-368 but not non-phospho-tau1-368 leads to a decrease in both body weight and survival rate of C57BL/6J mice. Intriguingly, although tau1-368-induced anxiety behavior in C57BL/6J mice is phosphorylation-independent, recognition memory of mice is impaired by phospho-tau1-368, but not by non-phospho-tau1-368. Immunofluorescence (IF) staining shows that overexpressing phospho-tau1-368 results in neuronal loss and gliosis in hippocampus, while the propagation of tau1-368 is phosphorylation-independent as measured by flowcytometry in vitro and IF in vivo. In conclusion, our findings reveal that phosphorylation of truncated tau promotes endogenous tau pathology and neurodegeneration.