Targeted dephosphorylation of Tau at the endogenous level promotes its association with microtubules.
Hyperphosphorylation of Tau is a contributory factor for Tauopathies, which constitute a spectrum of neurodegenerative disorders including Alzheimer's disease (AD). Inhibitors of Tau kinases or activators of the Tau phosphatase PP2A to reverse Tau hyperphosphorylation have shown limited therapeutic promise, due primarily to a lack of Tau selectivity. An innovative strategy to potentially circumvent these limitations would be to selectively target the dephosphorylation of phospho-residues on Tau. In this study, we provide evidence for targeted dephosphorylation of phospho-Tau at the endogenous level, including those known to promote Tau aggregation. By recruiting PPP1CA and PPP2CA Affinity-directed (Ad)-Phosphatases to Tau, we demonstrate highly selective targeted dephosphorylation of multiple phospho-residues on Tau in SK-N-MC neuroblastoma cells, leading to its stabilization in microtubules. Moreover, by using a heterobifunctional molecule termed BDPIC (bromoTAG-dTAG proximity-inducing chimera) in cells harbouring bromoTAG and dTAG knockins on Tau and PPP2CA, respectively, we demonstrate highly selective dephosphorylation phospho-residues on Tau.