Phosphorylated peptide Tau-pT181 induced tau aggregation and cognitive dysfunction

BackgroundClinically, phosphorylation of Tau protein at threonine 181 (p-Tau181) acts as a crucial biomarker for AD detection. However, the mechanisms through which Tau phosphorylation at threonine (Thr)181 site leads to Tau aggregation and corresponding neuropathological changes remain unclear.ObjectiveTo investigate the effect of the phosphorylated tau peptide at Thr181 on tau aggregation, synaptic and cognitive impairments.MethodsWe synthesized the phosphorylated tau peptide Tau-pT181 and the non-phosphorylated tau peptide Tau-nT181, and verified their effects on the aggregation of the Tau repeat domain R3 fragment peptide and Tau pathology.ResultsThioflavin S assay showed that Tau-pT181 significantly promoted the aggregation of R3, whereas Tau-nT181 did not induce R3 aggregation. Moreover, Tau-pT181 not Tau-nT181 led to the aggregation of Tau protein in 293/tau cells and decreased synapse-associated proteins in primary hippocampal neurons. One month after injecting Tau-pT181 and Tau-nT181 respectively into the rat CA1 hippocampal region, we found that exclusively the phosphorylated peptide Tau-pT181 induced endogenous Tau aggregation, synaptic damage, neuronal loss, while Tau-pT181 group exhibited significant cognitive impairment compared with the normal saline rats. Transcriptome analysis of neurons differentiated from iPSCs treated with Tau-pT181/Tau-nT181 suggest that phosphorylated peptides had a greater impact on axonogenesis, neuronal development, and Wnt signaling pathway.ConclusionsThe present study offers the first direct evidence that Tau phosphorylation at Thr181 induces Tau aggregation, and Tau-pT181 directly leads to neuropathological alterations and cognitive impairments, and establishes a new theoretical foundation for Tau Thr181 phosphorylation site as a core diagnostic marker and therapeutic target for AD.