Abstract
The effects of membranes on the early-stage aggregation of amyloid β (Aβ) have come to light as potential mechanisms by which neurotoxic species are formed in Alzheimer’s disease. We have shown that direct Aβ-membrane interactions dramatically enhance the Aβ aggregation, allowing for oligomer assembly at physiologically low concentrations of the monomer. Membrane composition is also a crucial factor in this process. Our results showed that apart from phospholipids composition, cholesterol in membranes significantly enhances the aggregation kinetics. It has been reported that free cholesterol is present in plaques. Here we report that free cholesterol, along with its presence inside the membrane, further accelerate the aggregation process by producing aggregates more rapidly and of significantly larger sizes. These aggregates, which are formed on the lipid bilayer, are able to dissociate from the surface and accumulate in the bulk solution; the presence of free cholesterol accelerates this dissociation as well. All-atom molecular dynamics simulations show that cholesterol binds Aβ monomers and significantly changes the conformational sampling of Aβ monomer; more than doubling the fraction of low-energy conformations compared to those in the absence of cholesterol, which can contribute to the aggregation process. The results indicate that Aβ-lipid interaction is an important factor in the disease prone amyloid assembly process.
Highlights
The self-assembly of amyloid β (Aβ) is a process that results in the production of neurotoxic oligomer and fibrillar aggregates in Alzheimer’s disease [1,2]
10 nM Aβ(1-42) monomer solution with and without 100 nM Chol was deposited on the bilayer and time-lapse Atomic Force Microscopy (AFM) imaging was performed to visualize the on-surface aggregation process
To understand if the bilayer composition is important during aggregation with free Chol in solution, we assembled a mixed bilayer with Chol, PC-PS-Chol bilayer, and followed the aggregation of Aβ in the presence of free Chol on this bilayer
Summary
The self-assembly of amyloid β (Aβ) is a process that results in the production of neurotoxic oligomer and fibrillar aggregates in Alzheimer’s disease [1,2]. Computer modeling showed that Aβ(1-42) has an elevated affinity to Chol-containing membranes, adopting a set of aggregation-prone conformations These studies led to an aggregation model with membranes playing a critical role in triggering the aggregation process and the disease state. The membrane composition is a factor controlling the aggregation process, so a change in membrane composition can shift the ratio between monomeric and aggregated states of Aβ This hypothesis is further strengthened by the data regarding the contribution of Chol, sphingomyelins, and gangliosides to the neurotoxicity of Aβ aggregates [13–15], which highlights these lipids as prime candidates for possible disease defining parameters. In the presence of free Chol, aggregates accumulate more rapidly in the bulk above the membrane bilayer These studies revealed a critical role of free Chol on the disease-prone aggregation of Aβ(1-42), suggesting that Chol can be a trigger of the aggregation process
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