Amyloid-β_25–35peptides aggregate into cross-β sheets in unsaturated anionic lipid membranes at high peptide concentrations

Abstract

One of the hallmarks of Alzheimer's disease is the formation of protein plaques in the brain, which mainly consist of amyloid-β peptides of different lengths. While the role of these plaques in the pathology of the disease is not clear, the mechanism behind peptide aggregation is a topic of intense research and discussion. Because of their simplicity, synthetic membranes are promising model systems to identify the elementary processes involved. We prepared unsaturated zwitterionic/anionic lipid membranes made of 1-palmitoyl-2-oleoyl-sn-glycero-phosphocholine (POPC) and 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine (DMPS) at concentrations of POPC/3 mol% DMPS containing 0 mol%, 3 mol%, 10 mol%, and 20 mol% amyloid-β25-35 peptides. Membrane-embedded peptide clusters were observed at peptide concentrations of 10 and 20 mol% with a typical cluster size of ∼11 μm. Cluster density increased with peptide concentration from 59 (±3) clusters per mm(2) to 920 (±64) clusters per mm(2), respectively. While monomeric peptides take an α-helical state when embedded in lipid bilayers at low peptide concentrations, the peptides in peptide clusters were found to form cross-β sheets and showed the characteristic pattern in X-ray experiments. The presence of the peptides was accompanied by an elastic distortion of the bilayers, which can induce a long range interaction between the peptides. The experimentally observed cluster patterns agree well with Monte Carlo simulations of long-range interacting peptides. This interaction may be the fundamental process behind cross-β sheet formation in membranes and these sheets may serve as seeds for further growth into amyloid fibrils.

The Molecular Structure of Human Red Blood Cell Membranes from Highly Oriented, Solid Supported Multi-Lamellar Membranes

“…2(d). These peaks fit well to distances between peptides and lipids, as observed in previous investigations in single and multi-component artificial and biological membranes171820212223. The lipid in-plane peaks are the result of a hexagonal packing of the lipid tails in the hydrophobic membrane core (planar group p6)16.…”

“…This density profile is well described by α -helical coiled-coil peptides, which are embedded in the membranes20, as will be discussed below, and was assigned to domains of integral proteins.…”

The Molecular Structure of Human Red Blood Cell Membranes From Highly Oriented, Solid Supported Multi-Lamellar Membranes

“…These techniques are ideally suited to study molecular structure and dynamical properties of membranes 13,21,[39][40][41][42][43][44][45][46] . The approach has advanced significantly during the past decades and is now used to study complex, multi-component membranes and their interaction with drugs, small molecules 13,20,26,37,[47][48][49][50][51][52][53] , bacteria 54,55 , and in particular lipid rafts, i.e. functional lipid domains 16,17,[56][57][58][59][60] .…”

“…Membrane peptides are often organized in bundles, whose structure is dominated by α-helical coiled-coils 20,[27][28][29][30] . Coiled coils consist of α-helices wind together to form a ropelike structure stabilized by hydrophobic interactions, and this structure is found in about 10% of the proteins in the human genome 31 .…”

A Cytosolic Amphiphilic α-Helix Controls the Activity of the Bile Acid-sensitive Ion Channel (BASIC)

“…After drying, the membrane samples were placed in vacuum at 313 K for 12 h to remove all traces of solvent. Samples were then placed in a sealed container containing an open vial of pure water and incubated at 303 K for 24 h. This procedure results in highly oriented multilamellar membrane stacks and a uniform coverage of the silicon substrates (34,36,46,47). About 3000 highly oriented stacked membranes with a total thickness of ϳ10 m are produced using this protocol.…”