ABSTRACT
Formation of amyloid-beta (Aß) 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 Aß oligomer formed in a membrane mimicking environment, namely an Aß(1-42) tetramer, which comprises a six stranded ß-sheet core. The two faces of the ß-sheet core are hydrophobic and surrounded by the membrane-mimicking environment while the edges are hydrophilic and solvent-exposed. By increasing the concentration of Aß(1-42) in the sample, Aß(1-42) octamers are also formed, made by two Aß(1-42) tetramers facing each other forming a ß-sandwich structure. Notably, Aß(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 ß-sheets edges of the oligomers.
