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Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage

Formation of amyloid-beta (Aβ) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimerʼs disease (AD). Here, we present the three-dimensional structure of an Aβ oligomer formed in a membrane mimicking environment, namely an Aβ(1-42) tetramer, which comprises...

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Autores principales: Ciudad, Sonia, Puig, Eduard, Botzanowski, Thomas, Meigooni, Moeen, Arango, Andres S., Do, Jimmy, Mayzel, Maxim, Bayoumi, Mariam, Chaignepain, Stéphane, Maglia, Giovanni, Cianferani, Sarah, Orekhov, Vladislav, Tajkhorshid, Emad, Bardiaux, Benjamin, Carulla, Natàlia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296003/
https://www.ncbi.nlm.nih.gov/pubmed/32541820
http://dx.doi.org/10.1038/s41467-020-16566-1
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author Ciudad, Sonia
Puig, Eduard
Botzanowski, Thomas
Meigooni, Moeen
Arango, Andres S.
Do, Jimmy
Mayzel, Maxim
Bayoumi, Mariam
Chaignepain, Stéphane
Maglia, Giovanni
Cianferani, Sarah
Orekhov, Vladislav
Tajkhorshid, Emad
Bardiaux, Benjamin
Carulla, Natàlia
author_facet Ciudad, Sonia
Puig, Eduard
Botzanowski, Thomas
Meigooni, Moeen
Arango, Andres S.
Do, Jimmy
Mayzel, Maxim
Bayoumi, Mariam
Chaignepain, Stéphane
Maglia, Giovanni
Cianferani, Sarah
Orekhov, Vladislav
Tajkhorshid, Emad
Bardiaux, Benjamin
Carulla, Natàlia
author_sort Ciudad, Sonia
collection PubMed
description Formation of amyloid-beta (Aβ) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimerʼs disease (AD). Here, we present the three-dimensional structure of an Aβ oligomer formed in a membrane mimicking environment, namely an Aβ(1-42) tetramer, which comprises a six stranded β-sheet core. The two faces of the β-sheet core are hydrophobic and surrounded by the membrane-mimicking environment while the edges are hydrophilic and solvent-exposed. By increasing the concentration of Aβ(1-42) in the sample, Aβ(1-42) octamers are also formed, made by two Aβ(1-42) tetramers facing each other forming a β-sandwich structure. Notably, Aβ(1-42) tetramers and octamers inserted into lipid bilayers as well-defined pores. To establish oligomer structure-membrane activity relationships, molecular dynamics simulations were carried out. These studies revealed a mechanism of membrane disruption in which water permeation occurred through lipid-stabilized pores mediated by the hydrophilic residues located on the core β-sheets edges of the oligomers.
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spelling pubmed-72960032020-06-19 Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage Ciudad, Sonia Puig, Eduard Botzanowski, Thomas Meigooni, Moeen Arango, Andres S. Do, Jimmy Mayzel, Maxim Bayoumi, Mariam Chaignepain, Stéphane Maglia, Giovanni Cianferani, Sarah Orekhov, Vladislav Tajkhorshid, Emad Bardiaux, Benjamin Carulla, Natàlia Nat Commun Article Formation of amyloid-beta (Aβ) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimerʼs disease (AD). Here, we present the three-dimensional structure of an Aβ oligomer formed in a membrane mimicking environment, namely an Aβ(1-42) tetramer, which comprises a six stranded β-sheet core. The two faces of the β-sheet core are hydrophobic and surrounded by the membrane-mimicking environment while the edges are hydrophilic and solvent-exposed. By increasing the concentration of Aβ(1-42) in the sample, Aβ(1-42) octamers are also formed, made by two Aβ(1-42) tetramers facing each other forming a β-sandwich structure. Notably, Aβ(1-42) tetramers and octamers inserted into lipid bilayers as well-defined pores. To establish oligomer structure-membrane activity relationships, molecular dynamics simulations were carried out. These studies revealed a mechanism of membrane disruption in which water permeation occurred through lipid-stabilized pores mediated by the hydrophilic residues located on the core β-sheets edges of the oligomers. Nature Publishing Group UK 2020-06-15 /pmc/articles/PMC7296003/ /pubmed/32541820 http://dx.doi.org/10.1038/s41467-020-16566-1 Text en © The Author(s) 2020 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
Ciudad, Sonia
Puig, Eduard
Botzanowski, Thomas
Meigooni, Moeen
Arango, Andres S.
Do, Jimmy
Mayzel, Maxim
Bayoumi, Mariam
Chaignepain, Stéphane
Maglia, Giovanni
Cianferani, Sarah
Orekhov, Vladislav
Tajkhorshid, Emad
Bardiaux, Benjamin
Carulla, Natàlia
Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage
title Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage
title_full Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage
title_fullStr Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage
title_full_unstemmed Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage
title_short Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage
title_sort aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296003/
https://www.ncbi.nlm.nih.gov/pubmed/32541820
http://dx.doi.org/10.1038/s41467-020-16566-1
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