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Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease
Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases including Alzheimer’s disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Her...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224595/ https://www.ncbi.nlm.nih.gov/pubmed/25326800 http://dx.doi.org/10.1038/nm.3700 |
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author | Zhang, Zhentao Song, Mingke Liu, Xia Kang, Seong Su Kwon, Il-Sun Duong, Duc M. Seyfried, Nicholas T. Hu, William T. Liu, Zhixue Wang, Jian-zhi Cheng, Liming Sun, Yi E. Yu, Shan Ping Levey, Allan I. Ye, Keqiang |
author_facet | Zhang, Zhentao Song, Mingke Liu, Xia Kang, Seong Su Kwon, Il-Sun Duong, Duc M. Seyfried, Nicholas T. Hu, William T. Liu, Zhixue Wang, Jian-zhi Cheng, Liming Sun, Yi E. Yu, Shan Ping Levey, Allan I. Ye, Keqiang |
author_sort | Zhang, Zhentao |
collection | PubMed |
description | Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases including Alzheimer’s disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is activated during aging and proteolytically degrades tau, abolishes its microtubule assembly function, induces tau aggregation, and triggers neurodegeneration. AEP is upregulated and active during aging, and is activated in tau P301S transgenic mice and human AD brain, leading to tau truncation in NFTs. Deletion of AEP from tau P301S transgenic mice substantially reduces tau hyperphosphorylation, alleviates the synapse loss and rescues impaired hippocampal synaptic function and the cognitive deficits. Infection of uncleavable tau N255AN368A mutant rescues tau P301S-induced pathological and behavioral defects. Together, these observations indicate that AEP acts as a crucial mediator of tau-related clinical and neuropathological changes in neurodegenerative diseases. Inhibition of AEP may be therapeutically useful for treating tau-mediated neurodegenerative diseases. |
format | Online Article Text |
id | pubmed-4224595 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-42245952015-05-01 Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease Zhang, Zhentao Song, Mingke Liu, Xia Kang, Seong Su Kwon, Il-Sun Duong, Duc M. Seyfried, Nicholas T. Hu, William T. Liu, Zhixue Wang, Jian-zhi Cheng, Liming Sun, Yi E. Yu, Shan Ping Levey, Allan I. Ye, Keqiang Nat Med Article Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases including Alzheimer’s disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is activated during aging and proteolytically degrades tau, abolishes its microtubule assembly function, induces tau aggregation, and triggers neurodegeneration. AEP is upregulated and active during aging, and is activated in tau P301S transgenic mice and human AD brain, leading to tau truncation in NFTs. Deletion of AEP from tau P301S transgenic mice substantially reduces tau hyperphosphorylation, alleviates the synapse loss and rescues impaired hippocampal synaptic function and the cognitive deficits. Infection of uncleavable tau N255AN368A mutant rescues tau P301S-induced pathological and behavioral defects. Together, these observations indicate that AEP acts as a crucial mediator of tau-related clinical and neuropathological changes in neurodegenerative diseases. Inhibition of AEP may be therapeutically useful for treating tau-mediated neurodegenerative diseases. 2014-10-19 2014-11 /pmc/articles/PMC4224595/ /pubmed/25326800 http://dx.doi.org/10.1038/nm.3700 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Zhang, Zhentao Song, Mingke Liu, Xia Kang, Seong Su Kwon, Il-Sun Duong, Duc M. Seyfried, Nicholas T. Hu, William T. Liu, Zhixue Wang, Jian-zhi Cheng, Liming Sun, Yi E. Yu, Shan Ping Levey, Allan I. Ye, Keqiang Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease |
title | Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease |
title_full | Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease |
title_fullStr | Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease |
title_full_unstemmed | Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease |
title_short | Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease |
title_sort | cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in alzheimer’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224595/ https://www.ncbi.nlm.nih.gov/pubmed/25326800 http://dx.doi.org/10.1038/nm.3700 |
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