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Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms

Protein aggregation is a complex process resulting in the formation of heterogeneous mixtures of aggregate populations that are closely linked to neurodegenerative conditions, such as Alzheimer’s disease. Here, we find that soluble aggregates formed at different stages of the aggregation process of...

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Autores principales: De, Suman, Wirthensohn, David C., Flagmeier, Patrick, Hughes, Craig, Aprile, Francesco A., Ruggeri, Francesco S., Whiten, Daniel R., Emin, Derya, Xia, Zengjie, Varela, Juan A., Sormanni, Pietro, Kundel, Franziska, Knowles, Tuomas P. J., Dobson, Christopher M., Bryant, Clare, Vendruscolo, Michele, Klenerman, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449370/
https://www.ncbi.nlm.nih.gov/pubmed/30948723
http://dx.doi.org/10.1038/s41467-019-09477-3
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author De, Suman
Wirthensohn, David C.
Flagmeier, Patrick
Hughes, Craig
Aprile, Francesco A.
Ruggeri, Francesco S.
Whiten, Daniel R.
Emin, Derya
Xia, Zengjie
Varela, Juan A.
Sormanni, Pietro
Kundel, Franziska
Knowles, Tuomas P. J.
Dobson, Christopher M.
Bryant, Clare
Vendruscolo, Michele
Klenerman, David
author_facet De, Suman
Wirthensohn, David C.
Flagmeier, Patrick
Hughes, Craig
Aprile, Francesco A.
Ruggeri, Francesco S.
Whiten, Daniel R.
Emin, Derya
Xia, Zengjie
Varela, Juan A.
Sormanni, Pietro
Kundel, Franziska
Knowles, Tuomas P. J.
Dobson, Christopher M.
Bryant, Clare
Vendruscolo, Michele
Klenerman, David
author_sort De, Suman
collection PubMed
description Protein aggregation is a complex process resulting in the formation of heterogeneous mixtures of aggregate populations that are closely linked to neurodegenerative conditions, such as Alzheimer’s disease. Here, we find that soluble aggregates formed at different stages of the aggregation process of amyloid beta (Aβ42) induce the disruption of lipid bilayers and an inflammatory response to different extents. Further, by using gradient ultracentrifugation assay, we show that the smaller aggregates are those most potent at inducing membrane permeability and most effectively inhibited by antibodies binding to the C-terminal region of Aβ42. By contrast, we find that the larger soluble aggregates are those most effective at causing an inflammatory response in microglia cells and more effectively inhibited by antibodies targeting the N-terminal region of Aβ42. These findings suggest that different toxic mechanisms driven by different soluble aggregated species of Aβ42 may contribute to the onset and progression of Alzheimer’s disease.
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spelling pubmed-64493702019-04-08 Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms De, Suman Wirthensohn, David C. Flagmeier, Patrick Hughes, Craig Aprile, Francesco A. Ruggeri, Francesco S. Whiten, Daniel R. Emin, Derya Xia, Zengjie Varela, Juan A. Sormanni, Pietro Kundel, Franziska Knowles, Tuomas P. J. Dobson, Christopher M. Bryant, Clare Vendruscolo, Michele Klenerman, David Nat Commun Article Protein aggregation is a complex process resulting in the formation of heterogeneous mixtures of aggregate populations that are closely linked to neurodegenerative conditions, such as Alzheimer’s disease. Here, we find that soluble aggregates formed at different stages of the aggregation process of amyloid beta (Aβ42) induce the disruption of lipid bilayers and an inflammatory response to different extents. Further, by using gradient ultracentrifugation assay, we show that the smaller aggregates are those most potent at inducing membrane permeability and most effectively inhibited by antibodies binding to the C-terminal region of Aβ42. By contrast, we find that the larger soluble aggregates are those most effective at causing an inflammatory response in microglia cells and more effectively inhibited by antibodies targeting the N-terminal region of Aβ42. These findings suggest that different toxic mechanisms driven by different soluble aggregated species of Aβ42 may contribute to the onset and progression of Alzheimer’s disease. Nature Publishing Group UK 2019-04-04 /pmc/articles/PMC6449370/ /pubmed/30948723 http://dx.doi.org/10.1038/s41467-019-09477-3 Text en © The Author(s) 2019 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
De, Suman
Wirthensohn, David C.
Flagmeier, Patrick
Hughes, Craig
Aprile, Francesco A.
Ruggeri, Francesco S.
Whiten, Daniel R.
Emin, Derya
Xia, Zengjie
Varela, Juan A.
Sormanni, Pietro
Kundel, Franziska
Knowles, Tuomas P. J.
Dobson, Christopher M.
Bryant, Clare
Vendruscolo, Michele
Klenerman, David
Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms
title Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms
title_full Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms
title_fullStr Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms
title_full_unstemmed Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms
title_short Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms
title_sort different soluble aggregates of aβ42 can give rise to cellular toxicity through different mechanisms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449370/
https://www.ncbi.nlm.nih.gov/pubmed/30948723
http://dx.doi.org/10.1038/s41467-019-09477-3
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