Effects of Lipid Membrane Curvatures on Binding, Secondary Structure, and Aggregation of Amyloid-Beta Protein

Abstract

Conversion of amyloid-beta (Abeta) protein from a non-toxic monomer into the toxic aggregates is the possible pathogenic pathways in Alzheimer's disease. Recent studies have suggested that lipid membranes play key roles in protein aggregation. It has been demonstrated that Abeta accumulated and formed amyloid fibrils in specific intra- or extracellular membrane structures such as intraluminal vesicles of multivesicular bodies (MVBs) and exosomes with a diameter that ranges from 30 to 80 nm. These studies raise the possibility that Abeta preferentially binds to small-sized intra- or extracellular vesicles with a high membrane curvature, although the presence of specific lipid components might also influence the interaction. Indeed, it has been reported that small lipid vesicles (≤50 nm) composed of PC accelerated Abeta fibrillation. However, the binding modes and the mechanisms of Abeta aggregation on lipid vesicles of high curvature are not fully understood. Here, we observed that a high positive curvature of lipid vesicles with diameters of ∼30 nm enhanced the binding of Abeta with anionic PG membranes in the liquid crystalline phase and with zwitterionic PC membranes in the gel phase. The binding modes of Abeta to these membranes differ in terms of the depth of the protein in the membrane and of the protein secondary structure. Amyloid fibril formation of Abeta was accelerated in the presence of the vesicles and at high protein-to-lipid ratios. Under these conditions, the protein highly accumulated on the surfaces, as demonstrated by high (∼10ˆ7 Mˆ-1) binding constants. Our findings suggest that packing defects on membranes with high curvatures might result in the accumulation of toxic protein aggregates.