TCB Publications - Abstract
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. Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage. Nature Communications, 11, 2020. (PMC: PMC7296003)
) 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 A
oligomer formed in a membrane mimicking environment, namely an A(1-
42) tetramer, which comprises a six stranded -sheet core. The two
faces of the -sheet core are hydrophobic and surrounded by the
membrane-mimicking environment while the edges are hydrophilic and solvent-
exposed. By increasing the concentration of A(1-42) in the sample,
A(1-42) octamers are also formed, made by two A(1-42)
tetramers facing each other forming a -sandwich structure. Notably,
A(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 -sheets edges of the oligomers.
