Molecular Insights into the Aβ-42 Tetramer-Induced Disruptive Effects on a Model Phospholipid Membrane

Formation of pores in neuronal membranes by amyloid-β (Aβ) oligomers is believed to be the origin behind neurotoxicity in Alzheimer’s disease (AD). However, despite significant efforts, high-resolution characterizations of the pore-forming Aβ oligomers from experimental studies have been hindered due to structural heterogeneity of such aggregated oligomers. Consequently, efforts have been made to characterize the aggregated oligomers that develop within a membrane environment. Attempts have been made in this study to probe the microscopic properties of the three-dimensional structure of an Aβ oligomer, specifically an Aβ-42 tetramer present in a membrane-mimicking environment. The tetramer comprises of eight antiparallel β strands forming an Aβ-42 barrel. Atomistic molecular dynamics simulations at constant temperature and pressure (NPT) have been carried out on a fully hydrated liquid-crystalline lamellar phase of dipalmitoylphosphatidylcholine (DPPC) lipid bilayer with an Aβ-42 tetramer embedded into it forming a pore. The results were compared with that of a fully hydrated pure DPPC bilayer system. Based on the calculations, we have been able to successfully quantify the disruptions in the bilayer structure caused by the peptide tetramer through conformational rearrangements of the lipid hydrocarbon chains. We believe that the results presented can quantitatively provide fundamental molecular-level insights into the detrimental effects of pore-forming Aβ-42 on membrane environment, which in turn, may have important implications on Alzheimer’s disease.