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Accumulation of human full-length tau induces degradation of nicotinic acetylcholine receptor α4 via activating calpain-2

Cholinergic impairments and tau accumulation are hallmark pathologies in sporadic Alzheimer’s disease (AD), however, the intrinsic link between tau accumulation and cholinergic deficits is missing. Here, we found that overexpression of human wild-type full-length tau (termed hTau) induced a signific...

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Autores principales: Yin, Yaling, Wang, Yali, Gao, Di, Ye, Jinwang, Wang, Xin, Fang, Lin, Wu, Dongqin, Pi, Guilin, Lu, Chengbiao, Zhou, Xin-Wen, Yang, Ying, Wang, Jian-Zhi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899694/
https://www.ncbi.nlm.nih.gov/pubmed/27277673
http://dx.doi.org/10.1038/srep27283
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author Yin, Yaling
Wang, Yali
Gao, Di
Ye, Jinwang
Wang, Xin
Fang, Lin
Wu, Dongqin
Pi, Guilin
Lu, Chengbiao
Zhou, Xin-Wen
Yang, Ying
Wang, Jian-Zhi
author_facet Yin, Yaling
Wang, Yali
Gao, Di
Ye, Jinwang
Wang, Xin
Fang, Lin
Wu, Dongqin
Pi, Guilin
Lu, Chengbiao
Zhou, Xin-Wen
Yang, Ying
Wang, Jian-Zhi
author_sort Yin, Yaling
collection PubMed
description Cholinergic impairments and tau accumulation are hallmark pathologies in sporadic Alzheimer’s disease (AD), however, the intrinsic link between tau accumulation and cholinergic deficits is missing. Here, we found that overexpression of human wild-type full-length tau (termed hTau) induced a significant reduction of α4 subunit of nicotinic acetylcholine receptors (nAChRs) with an increased cleavage of the receptor producing a ~55kDa fragment in primary hippocampal neurons and in the rat brains, meanwhile, the α4 nAChR currents decreased. Further studies demonstrated that calpains, including calpain-1 and calpain-2, were remarkably activated with no change of caspase-3, while simultaneous suppression of calpain-2 by selective calpain-2 inhibitor but not calpain-1 attenuated the hTau-induced degradation of α4 nAChR. Finally, we demonstrated that hTau accumulation increased the basal intracellular calcium level in primary hippocampal neurons. We conclude that the hTau accumulation inhibits nAChRs α4 by activating calpain-2. To our best knowledge, this is the first evidence showing that the intracellular accumulation of tau causes cholinergic impairments.
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spelling pubmed-48996942016-06-13 Accumulation of human full-length tau induces degradation of nicotinic acetylcholine receptor α4 via activating calpain-2 Yin, Yaling Wang, Yali Gao, Di Ye, Jinwang Wang, Xin Fang, Lin Wu, Dongqin Pi, Guilin Lu, Chengbiao Zhou, Xin-Wen Yang, Ying Wang, Jian-Zhi Sci Rep Article Cholinergic impairments and tau accumulation are hallmark pathologies in sporadic Alzheimer’s disease (AD), however, the intrinsic link between tau accumulation and cholinergic deficits is missing. Here, we found that overexpression of human wild-type full-length tau (termed hTau) induced a significant reduction of α4 subunit of nicotinic acetylcholine receptors (nAChRs) with an increased cleavage of the receptor producing a ~55kDa fragment in primary hippocampal neurons and in the rat brains, meanwhile, the α4 nAChR currents decreased. Further studies demonstrated that calpains, including calpain-1 and calpain-2, were remarkably activated with no change of caspase-3, while simultaneous suppression of calpain-2 by selective calpain-2 inhibitor but not calpain-1 attenuated the hTau-induced degradation of α4 nAChR. Finally, we demonstrated that hTau accumulation increased the basal intracellular calcium level in primary hippocampal neurons. We conclude that the hTau accumulation inhibits nAChRs α4 by activating calpain-2. To our best knowledge, this is the first evidence showing that the intracellular accumulation of tau causes cholinergic impairments. Nature Publishing Group 2016-06-09 /pmc/articles/PMC4899694/ /pubmed/27277673 http://dx.doi.org/10.1038/srep27283 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Yin, Yaling
Wang, Yali
Gao, Di
Ye, Jinwang
Wang, Xin
Fang, Lin
Wu, Dongqin
Pi, Guilin
Lu, Chengbiao
Zhou, Xin-Wen
Yang, Ying
Wang, Jian-Zhi
Accumulation of human full-length tau induces degradation of nicotinic acetylcholine receptor α4 via activating calpain-2
title Accumulation of human full-length tau induces degradation of nicotinic acetylcholine receptor α4 via activating calpain-2
title_full Accumulation of human full-length tau induces degradation of nicotinic acetylcholine receptor α4 via activating calpain-2
title_fullStr Accumulation of human full-length tau induces degradation of nicotinic acetylcholine receptor α4 via activating calpain-2
title_full_unstemmed Accumulation of human full-length tau induces degradation of nicotinic acetylcholine receptor α4 via activating calpain-2
title_short Accumulation of human full-length tau induces degradation of nicotinic acetylcholine receptor α4 via activating calpain-2
title_sort accumulation of human full-length tau induces degradation of nicotinic acetylcholine receptor α4 via activating calpain-2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899694/
https://www.ncbi.nlm.nih.gov/pubmed/27277673
http://dx.doi.org/10.1038/srep27283
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