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

Abstract : Formation of amyloid-beta (Aβ) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimer's 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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Submitted on : Thursday, June 18, 2020 - 6:34:24 PM
Last modification on : Saturday, June 20, 2020 - 3:34:02 AM

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Sonia Ciudad, Eduard Puig, Thomas Botzanowski, Moeen Meigooni, Andres Arango, et al.. Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage. Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.3014. ⟨10.1038/s41467-020-16566-1⟩. ⟨pasteur-02874153⟩

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