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

Formation of amyloid-beta (A beta) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimers disease (AD). Here, we present the three-dimensional structure of an A beta oligomer formed in a membrane mimicking environment, namely an A beta(1-42) tetramer, which comprises a six stranded beta-sheet core. The two faces of the beta-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 beta(1-42) in the sample, A beta(1-42) octamers are also formed, made by two A beta(1-42) tetramers facing each other forming a beta-sandwich structure. Notably, A beta(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 beta-sheets edges of the oligomers.