Targeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality

Microtubule-associated protein tau is essential for microtubule assembly and stabilization. Hyperphosphorylation of the microtubule-associated protein tau plays an important pathological role in the development of Alzheimer's disease and other tauopathies. In vivo studies using kinase inhibitors suggest that reducing tau phosphorylation levels has therapeutic potential; however, such approaches showed limited benefits. We sought to further develop our phosphorylation targeting chimera (PhosTAC) technology to specifically induce tau dephosphorylation. Herein, we use small molecule-based PhosTACs to recruit tau to PP2A, a native tau phosphatase. PhosTACs induced the formation of a stable ternary complex, leading to rapid, efficient, and sustained tau dephosphorylation, which also correlated with the enhanced downregulation of tau protein. Mass spectrometry data validated that PhosTACs downregulated multiple phosphorylation sites of tau. We believe that PhosTAC possesses several advantages over current strategies to modulate tau phosphorylation and represents a new avenue for disease-modifying therapies for tauopathies.

Automated summary

Microtubule-associated protein tau is crucial for microtubule assembly and stabilization. Tau hyperphosphorylation is implicated in the development of Alzheimer's disease and tauopathies. In this study, we used small molecule-based PhosTACs to induce efficient and sustained tau dephosphorylation by recruiting tau to PP2A, a native tau phosphatase. Mass spectrometry data validated that PhosTACs downregulated multiple phosphorylation sites of tau. Our findings suggest that PhosTACs represent a potential avenue for disease-modifying therapies for tauopathies.