A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies.

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.

• Authors: Jie Zheng, Na Tian, Fei Liu, Yidian Zhang, Jingfen Su, Yang Gao, Mingmin Deng, Linyu Wei, Jingwang Ye, Honglian Li, Jian-Zhi Wang
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 6 Issue 1 Pg. 269 (07 14 2021) ISSN: 2059-3635 [Electronic] England
• PMID: 34262014 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Peptides
• PPP2R3A protein, human
• Protein Phosphatase 2
• tau Proteins

Topics

• Animals
• Humans
• Mice
• Rats
• Alzheimer Disease (drug therapy, genetics, pathology)
• Brain (drug effects)
• Disease Models, Animal
• Hippocampus (drug effects)
• Mice, Transgenic
• Microtubules (drug effects, genetics)
• Molecular Targeted Therapy
• Peptides (chemical synthesis, pharmacology)
• Phosphorylation (drug effects)
• Primary Cell Culture
• Protein Binding (drug effects)
• Protein Phosphatase 2 (antagonists & inhibitors, genetics)
• tau Proteins (genetics)
• Tauopathies (drug therapy, genetics, pathology)