A Small‐Molecule DEPTAC Rescues Cognitive Deficits by Targeted Dephosphorylation of Pathological Tau

ABSTRACT Accumulation of hyperphosphorylated Tau (p‐Tau) is a central driver of neurodegeneration in Alzheimer's disease (AD). Addressing the limitations of current therapeutics, we developed TP2, a small‐molecule DEPhosphorylation‐TArgeting Chimera (DEPTAC). TP2 is engineered to physically tether endogenous PP2A to Tau, facilitating targeted dephosphorylation. Mechanistically, TP2 induces ternary complex formation and potently reduces p‐Tau in neurons. Systemic administration of TP2 in distinct tauopathy mouse models (P301L and AAV‐hTau‐N368) significantly lowered brain p‐Tau levels, oligomers, and neurofibrillary tangles without altering global PP2A activity. Crucially, by rebalancing the phosphorylation of Tau, TP2 restored Tau's physiological function, as evidenced by the preservation of neuronal morphology, synaptic integrity, and microtubule stability. TP2 also ameliorated the dysregulated neuroimmune microenvironment. Consequently, TP2 treatment robustly reversed cognitive deficits in multiple behavioral paradigms. These findings establish TP2 as a promising therapeutic candidate that targets upstream pathological phosphorylation to halt neurodegeneration and restore cognitive function.