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A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies
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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280143/ https://www.ncbi.nlm.nih.gov/pubmed/34262014 http://dx.doi.org/10.1038/s41392-021-00669-2 |
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author | Zheng, Jie Tian, Na Liu, Fei Zhang, Yidian Su, Jingfen Gao, Yang Deng, Mingmin Wei, Linyu Ye, Jingwang Li, Honglian Wang, Jian-Zhi |
author_facet | Zheng, Jie Tian, Na Liu, Fei Zhang, Yidian Su, Jingfen Gao, Yang Deng, Mingmin Wei, Linyu Ye, Jingwang Li, Honglian Wang, Jian-Zhi |
author_sort | Zheng, Jie |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8280143 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82801432021-07-19 A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies Zheng, Jie Tian, Na Liu, Fei Zhang, Yidian Su, Jingfen Gao, Yang Deng, Mingmin Wei, Linyu Ye, Jingwang Li, Honglian Wang, Jian-Zhi Signal Transduct Target Ther Article 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. Nature Publishing Group UK 2021-07-14 /pmc/articles/PMC8280143/ /pubmed/34262014 http://dx.doi.org/10.1038/s41392-021-00669-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Zheng, Jie Tian, Na Liu, Fei Zhang, Yidian Su, Jingfen Gao, Yang Deng, Mingmin Wei, Linyu Ye, Jingwang Li, Honglian Wang, Jian-Zhi A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies |
title | A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies |
title_full | A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies |
title_fullStr | A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies |
title_full_unstemmed | A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies |
title_short | A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies |
title_sort | novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280143/ https://www.ncbi.nlm.nih.gov/pubmed/34262014 http://dx.doi.org/10.1038/s41392-021-00669-2 |
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