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Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ(1–42) synaptotoxicity
Oligomeric Amyloid β(1–42) (Aβ) plays a crucial synaptotoxic role in Alzheimer’s disease, and hyperphosphorylated tau facilitates Aβ toxicity. The link between Aβ and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aβ acutely induces tubulin posttranslational...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626542/ https://www.ncbi.nlm.nih.gov/pubmed/28877993 http://dx.doi.org/10.1083/jcb.201701045 |
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author | Qu, Xiaoyi Yuan, Feng Ning Corona, Carlo Pasini, Silvia Pero, Maria Elena Gundersen, Gregg G. Shelanski, Michael L. Bartolini, Francesca |
author_facet | Qu, Xiaoyi Yuan, Feng Ning Corona, Carlo Pasini, Silvia Pero, Maria Elena Gundersen, Gregg G. Shelanski, Michael L. Bartolini, Francesca |
author_sort | Qu, Xiaoyi |
collection | PubMed |
description | Oligomeric Amyloid β(1–42) (Aβ) plays a crucial synaptotoxic role in Alzheimer’s disease, and hyperphosphorylated tau facilitates Aβ toxicity. The link between Aβ and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aβ acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by Aβ. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in Aβ-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau-mediated neuronal damage. |
format | Online Article Text |
id | pubmed-5626542 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-56265422018-04-02 Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ(1–42) synaptotoxicity Qu, Xiaoyi Yuan, Feng Ning Corona, Carlo Pasini, Silvia Pero, Maria Elena Gundersen, Gregg G. Shelanski, Michael L. Bartolini, Francesca J Cell Biol Research Articles Oligomeric Amyloid β(1–42) (Aβ) plays a crucial synaptotoxic role in Alzheimer’s disease, and hyperphosphorylated tau facilitates Aβ toxicity. The link between Aβ and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aβ acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by Aβ. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in Aβ-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau-mediated neuronal damage. The Rockefeller University Press 2017-10-02 /pmc/articles/PMC5626542/ /pubmed/28877993 http://dx.doi.org/10.1083/jcb.201701045 Text en © 2017 Qu et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Qu, Xiaoyi Yuan, Feng Ning Corona, Carlo Pasini, Silvia Pero, Maria Elena Gundersen, Gregg G. Shelanski, Michael L. Bartolini, Francesca Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ(1–42) synaptotoxicity |
title | Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ(1–42) synaptotoxicity |
title_full | Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ(1–42) synaptotoxicity |
title_fullStr | Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ(1–42) synaptotoxicity |
title_full_unstemmed | Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ(1–42) synaptotoxicity |
title_short | Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ(1–42) synaptotoxicity |
title_sort | stabilization of dynamic microtubules by mdia1 drives tau-dependent aβ(1–42) synaptotoxicity |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626542/ https://www.ncbi.nlm.nih.gov/pubmed/28877993 http://dx.doi.org/10.1083/jcb.201701045 |
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