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Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex

Microtubule-associated protein Tau can form protein aggregates transmissible within the brain, correlating with the progression of tauopathies in humans. The transmission of aggregates requires neuron-released Tau to interact with surface receptors on target cells. However, the underlying molecular...

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Detalles Bibliográficos
Autores principales: Wang, Peng, Ye, Yihong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782792/
https://www.ncbi.nlm.nih.gov/pubmed/33398028
http://dx.doi.org/10.1038/s41467-020-20322-w
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author Wang, Peng
Ye, Yihong
author_facet Wang, Peng
Ye, Yihong
author_sort Wang, Peng
collection PubMed
description Microtubule-associated protein Tau can form protein aggregates transmissible within the brain, correlating with the progression of tauopathies in humans. The transmission of aggregates requires neuron-released Tau to interact with surface receptors on target cells. However, the underlying molecular mechanisms in astrocytes and downstream effects are unclear. Here, using a spatially resolved proteomic mapping strategy, we show that integrin αV/β1 receptor binds recombinant human Tau, mediating the entry of Tau fibrils in astrocytes. The binding of distinct Tau species to the astrocytic αV/β1 receptor differentially activate integrin signaling. Furthermore, Tau-mediated activation of integrin signaling results in NFκB activation, causing upregulation of pro-inflammatory cytokines and chemokines, induction of a sub-group of neurotoxic astrocytic markers, and release of neurotoxic factors. Our findings suggest that filamentous recombinant human Tau-mediated activation of integrin signaling induces astrocyte conversion towards a neurotoxic state, providing a mechanistic insight into tauopathies.
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spelling pubmed-77827922021-01-11 Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex Wang, Peng Ye, Yihong Nat Commun Article Microtubule-associated protein Tau can form protein aggregates transmissible within the brain, correlating with the progression of tauopathies in humans. The transmission of aggregates requires neuron-released Tau to interact with surface receptors on target cells. However, the underlying molecular mechanisms in astrocytes and downstream effects are unclear. Here, using a spatially resolved proteomic mapping strategy, we show that integrin αV/β1 receptor binds recombinant human Tau, mediating the entry of Tau fibrils in astrocytes. The binding of distinct Tau species to the astrocytic αV/β1 receptor differentially activate integrin signaling. Furthermore, Tau-mediated activation of integrin signaling results in NFκB activation, causing upregulation of pro-inflammatory cytokines and chemokines, induction of a sub-group of neurotoxic astrocytic markers, and release of neurotoxic factors. Our findings suggest that filamentous recombinant human Tau-mediated activation of integrin signaling induces astrocyte conversion towards a neurotoxic state, providing a mechanistic insight into tauopathies. Nature Publishing Group UK 2021-01-04 /pmc/articles/PMC7782792/ /pubmed/33398028 http://dx.doi.org/10.1038/s41467-020-20322-w Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2021 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/.
spellingShingle Article
Wang, Peng
Ye, Yihong
Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex
title Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex
title_full Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex
title_fullStr Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex
title_full_unstemmed Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex
title_short Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex
title_sort filamentous recombinant human tau activates primary astrocytes via an integrin receptor complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782792/
https://www.ncbi.nlm.nih.gov/pubmed/33398028
http://dx.doi.org/10.1038/s41467-020-20322-w
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