Interaction of Monomeric Amyloid Beta-Protein (ABETA-42)with Bilayers Containing Anionic Phospholipids

Abstract

Alzheimer's disease (AD) is a late-onset neurological disorder with progressive loss of memory and cognitive abilities as a result of excessive neurodegeneration. AD is characterized by extracellular aggregates of β-amyloid (Aβ) peptides known as amyloid plaques. The toxicity of the peptide appears to require conversion of the monomeric form to an aggregated fibrillar species. Electrostatic interactions between Aβ and the phospholipid headgroup have been found to control the association and insertion of monomeric Aβ into membrane. To elucidate the molecular and structural details of Aβ-membrane association, we have used LUV and monolayers composed of sphingomyelin (SM), cholesterol (Ch) ± dimyristoyl phosphatidic acid (DMPA). Isothermal titration calorimetry (ITC), Langmuir monolayer experiments and molecular dynamics (MD) simulations have been performed. Using Langmuir monolayers and ITC, our results indicate that Aβ(42) inserts in bilayers formed by SM/Ch/DMPA (40/40/20) and SM/Ch/DMPA (47.5/47.5/5), but less so in those consisting of SM/Ch in the absence of DMPA. The effect obtained by DMPA (5%) is more important than that of DMPA (20%). Moreover, the molecular dynamics simulations of Aβ42 on the surface of the phospholipid bilayer show different binding modes in models with varying DMPA ratios. The 5% DMPA surface binds to Aβ42 more strongly than the one containing 20% DMPA and conformational changes occur in the secondary structure. The 20% DMPA surface binds weakly, and the native secondary structure of Aβ42 is conserved. The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 212043.