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

Sonia Ciudad, Eduard Puig, Thomas Botzanowski, Moeen Meigooni, Andres S. Arango, Jimmy Do, Maxim Mayzel, Mariam Bayoumi, Stéphane Chaignepain, Giovanni Maglia, Sarah Cianferani, Vladislav Orekhov, Emad Tajkhorshid, Benjamin Bardiaux and Natàlia Carulla ()
Additional contact information
Sonia Ciudad: University of Bordeaux, CBMN (UMR 5248)—CNRS—IPB, Institut Européen de Chimie et Biologie
Eduard Puig: University of Bordeaux, CBMN (UMR 5248)—CNRS—IPB, Institut Européen de Chimie et Biologie
Thomas Botzanowski: Université de Strasbourg, CNRS UMR7178, IPHC
Moeen Meigooni: University of Illinois at Urbana-Champaign
Andres S. Arango: University of Illinois at Urbana-Champaign
Jimmy Do: University of Illinois at Urbana-Champaign
Maxim Mayzel: University of Gothenburg
Mariam Bayoumi: University of Leuven
Stéphane Chaignepain: University of Bordeaux, CBMN (UMR 5248)—CNRS—IPB, Institut Européen de Chimie et Biologie
Giovanni Maglia: University of Groningen
Sarah Cianferani: Université de Strasbourg, CNRS UMR7178, IPHC
Vladislav Orekhov: University of Gothenburg
Emad Tajkhorshid: University of Illinois at Urbana-Champaign
Benjamin Bardiaux: C3BI, Institut Pasteur; CNRS UMR3528; CNRS USR3756
Natàlia Carulla: University of Bordeaux, CBMN (UMR 5248)—CNRS—IPB, Institut Européen de Chimie et Biologie

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-16566-1

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