The Influence of Lipid Electric Charge on the Binding of Aβ(1–42) Amyloid Peptide to Bilayers in the Liquid-Ordered State

Abstract

The amyloidogenic Aβ peptides are widely considered as a pathogenic agent in Alzheimer’s disease. Aβ(1-42) would form aggregates of amyloid fibrils on the neuron plasma membranes, thus perturbing neuronal functionality. Conflicting data are available on the influence of bilayer order on Aβ(1-42) binding to membranes. In the present study, a biophysical approach was used in which isothermal calorimetry and surface pressure measurements were applied to explore the interaction of Aβ(1-42) in either monomeric, oligomeric, or fibrillar form with model membranes (bilayers or monolayers) in the liquid-ordered state that were either electrically neutral or negatively charged. In the latter case, this contained phosphatidic acid, cardiolipin, or ganglioside. The calorimetric studies showed that Aβ(1-42) fibrils, oligomers, and monomers could bind and/or be inserted into bilayers, irrespective of electric charge, in the liquid-ordered state, except that monomers could not interact with electrically neutral bilayers. The monolayer studies in the Langmuir balance demonstrated that Aβ(1-42) aggregation hindered peptide insertion into the monolayer, hindered insertion in the decreasing order of monomer > oligomer > fibril, and that lipid composition did not cause large differences in insertion, apart from a slight facilitation of monomer and oligomer insertion by gangliosides.

Understanding Aβ Peptide Binding to Lipid Membranes: A Biophysical Perspective

“…Ahyayauch et al expanded the applications of Langmuir monolayers to investigate the lipid interactions of Aβ42 [ 9 , 10 , 11 , 12 ]. They examined the binding of A42 peptide monomers to sphingomyelin/cholesterol (1:1 mol ratio) monolayers containing 5 mol% gangliosides (GM1, GT1b, or a mixture of brain gangliosides) [ 10 ].…”

“…Ahyayauch et al also examined the state of aggregation of Aβ42 (monomer, oligomer, or fibril) and its influence on the interaction with sphingomyelin/cholesterol (with or without gangliosides) in lipid monolayers [ 11 , 12 ]. They found that all three peptide preparations could be inserted into lipid monolayers of any composition and initial π in the 10–30 mN/m range, although fibrils were less capable of doing so than oligomers or monomers, with their maximum initial π value being ≈25 mN/m.…”

“…In recent years, Ahyayauch et al conducted extensive and systematic calorimetric measurements of the interaction between Aβ42 peptide and lipids, particularly in the form of liposomes (large unilamellar vesicles, LUVs) [ 8 , 10 , 11 , 12 ]. They found that when LUVs contained sphingomyelin (SM) and cholesterol (Chol) without negatively charged lipids, no measurable heats of interaction with monomeric Aβ were observed.…”

“…Lipid monolayers, spread over an air–water interface, can model various physical phenomena that are seen, or presumed to occur, in biomembranes [ 8 ]. These include phase transitions, changes in lateral diffusion, alterations in lateral compressibility/elasticity, and interactions that can influence lipid mixing, resulting in critical points as well as in immiscible or coexisting lateral phases (domains) [ 12 , 22 , 23 , 24 , 25 ]. Early studies focused on constructing lipid phase diagrams with mixtures of two lipid components [ 23 , 24 , 26 ], but more recent research has examined the phase behavior of “raft” ternary mixtures of phosphatidyl choline/sphingomyelin/cholesterol (PC/SM/Chol) using epifluorescence microscopy to monitor lipid distribution patterns [ 27 , 28 , 29 , 30 ].…”

“…Research has shown that cell membranes significantly accelerate Aβ aggregation (see, for example, [ 4 , 5 , 6 , 7 ] for reviews). Many of these studies, including those conducted by our laboratories [ 8 , 9 , 10 , 11 , 12 ], have investigated the interaction of β-amyloid with model membranes. The general consensus is that Aβ interacts with lipid surfaces, especially those containing anionic lipids, leading to a much faster aggregation rate compared to its behavior in a solution.…”