A Small‐Molecule DEPTAC Rescues Cognitive Deficits by Targeted Dephosphorylation of Pathological Tau
7 affiliations
- 1Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan China
- 2Institute For Translational Neuroscience Nantong First People's Hospital Southeast University Nantong Jiangsu China
- 3Institute of Structural Pharmacology & TCM Chemical Biology Fujian Key Laboratory of Chinese Materia Medica College of Pharmacy Fujian University of Traditional Chinese Medicine Fuzhou China
- 4Wuya College of Innovation School of Pharmacy Key Laboratory of Structure‐Based Drug Design & Discovery Ministry of Education Shenyang Pharmaceutical University Shenyang China
- 5Department of Rehabilitation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
- 6Department of Clinical Medicine School of Medicine Nanchang University Nanchang China
- 7Department of Pathology The First Affiliated Hospital of Zhengzhou University Zhengzhou China
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.
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BibTeX
@article{sun2026smallmolecule,
title = {{A Small‐Molecule DEPTAC Rescues Cognitive Deficits by Targeted Dephosphorylation of Pathological Tau}},
author = {Fei Sun and Yang Liu and Qiuzhi Zhou and Qingyuan Hu and Weixia Wang and Yue Xiao and Jingfen Su and Guanting Liu and Miaomiao Sun and Lixia Chen and Hua Li and Ying Yang and Jian‐Zhi Wang},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77088},
url = {https://doi.org/10.1002/advs.77088},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A Small‐Molecule DEPTAC Rescues Cognitive Deficits by Targeted Dephosphorylation of Pathological Tau
AU - Fei Sun
AU - Yang Liu
AU - Qiuzhi Zhou
AU - Qingyuan Hu
AU - Weixia Wang
AU - Yue Xiao
AU - Jingfen Su
AU - Guanting Liu
AU - Miaomiao Sun
AU - Lixia Chen
AU - Hua Li
AU - Ying Yang
AU - Jian‐Zhi Wang
PY - 2026
DA - 2026/08/11
JO - Advanced Science
DO - 10.1002/advs.77088
UR - https://doi.org/10.1002/advs.77088
AB - 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.
SN - 2198-3844
ER -