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

Author:

Ciudad SoniaORCID,Puig Eduard,Botzanowski Thomas,Meigooni Moeen,Arango Andres S.,Do Jimmy,Mayzel MaximORCID,Bayoumi Mariam,Chaignepain Stéphane,Maglia GiovanniORCID,Cianferani Sarah,Orekhov Vladislav,Tajkhorshid EmadORCID,Bardiaux BenjaminORCID,Carulla NatàliaORCID

Abstract

AbstractFormation 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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