Affiliations
- Department 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. zhengjie@zmu.edu.cn.
- Department of Pharmacology, Key Laboratory of Basic Pharmacology of Ministry of Education, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi, China. zhengjie@zmu.edu.cn.
- Department of Histology and Embryology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department 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.
- Department 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. wangjz@mail.hust.edu.cn.
- Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China. wangjz@mail.hust.edu.cn.
PMID: 34262014 PMCID: PMC8280143 DOI: 10.1038/s41392-021-00669-2
Abstract
Intraneuronal accumulation of hyperphosphorylated tau is a hallmark pathology shown in over twenty neurodegenerative disorders, collectively termed as tauopathies, including the most common Alzheimer's disease (AD). Therefore, selectively removing or reducing hyperphosphorylated tau is promising for therapies of AD and other tauopathies. Here, we designed and synthesized a novel DEPhosphorylation TArgeting Chimera (DEPTAC) to specifically facilitate the binding of tau to Bα-subunit-containing protein phosphatase 2A (PP2A-Bα), the most active tau phosphatase in the brain. The DEPTAC exhibited high efficiency in dephosphorylating tau at multiple AD-associated sites and preventing tau accumulation both in vitro and in vivo. Further studies revealed that DEPTAC significantly improved microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice with inducible overexpression of truncated and neurotoxic human tau N368. Our data provide a strategy for selective removal of the hyperphosphorylated tau, which sheds new light for the targeted therapy of AD and related-tauopathies.
