Free Cholesterol Accelerates Aβ Self-Assembly on Membranes at Physiological Concentration

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.

The intriguing dose-dependent effect of selected amphiphilic compounds on insulin amyloid aggregation: Focus on a cholesterol-based detergent, Chobimalt

“…Particularly important appears to be the role of hydrophobic interaction of amyloid-prone proteins/peptides with membranes and/or with the individual membrane components (Jelinek and Sheynis, 2010;Nault et al, 2013). It is currently accepted, that membrane composition is the factor controlling the aggregation process (Necula et al, 2003;Gorbenko and Kinnunen, 2006;Bucciantini et al, 2014;Banerjee et al, 2021;Hashemi et al, 2022). Lipid bilayers may act as conformational catalysts, favoring protein misfolding and inducing the growth of aggregation nuclei, early oligomers, and mature fibrils with specific biophysical, structural, and toxicity features (Bucciantini et al, 2014;Korshavn et al, 2017;Rangachari et al, 2018).…”

“…A significant effect of lipid bilayers has been investigated in detail for Aβ peptide aggregation (Matsuzaki, 2007;Lin et al, 2009;Korshavn et al, 2017;Iadanza et al, 2018;Hashemi et al, 2022;Mrdenovic et al, 2022). The strongest evidence causally linking cholesterol to AD is provided by experimental studies showing that adding or reducing cholesterol alters amyloid precursor protein (APP) and Aβ peptide levels (McLaurin et al, 2003;Wood et al, 2003;Lin et al, 2009;Banerjee et al, 2021;Hashemi et al, 2022).…”

“…A significant effect of lipid bilayers has been investigated in detail for Aβ peptide aggregation (Matsuzaki, 2007;Lin et al, 2009;Korshavn et al, 2017;Iadanza et al, 2018;Hashemi et al, 2022;Mrdenovic et al, 2022). The strongest evidence causally linking cholesterol to AD is provided by experimental studies showing that adding or reducing cholesterol alters amyloid precursor protein (APP) and Aβ peptide levels (McLaurin et al, 2003;Wood et al, 2003;Lin et al, 2009;Banerjee et al, 2021;Hashemi et al, 2022). For example, accumulation of cholesterol in membranes is associated with AD development, suggesting that insertion of cholesterol into membranes may initiate the Aβ aggregation, and significantly enhances the aggregation kinetics of Aβ (Banerjee et al, 2021;Hashemi et al, 2022).…”

“…The strongest evidence causally linking cholesterol to AD is provided by experimental studies showing that adding or reducing cholesterol alters amyloid precursor protein (APP) and Aβ peptide levels (McLaurin et al, 2003;Wood et al, 2003;Lin et al, 2009;Banerjee et al, 2021;Hashemi et al, 2022). For example, accumulation of cholesterol in membranes is associated with AD development, suggesting that insertion of cholesterol into membranes may initiate the Aβ aggregation, and significantly enhances the aggregation kinetics of Aβ (Banerjee et al, 2021;Hashemi et al, 2022). The enhanced aggregation propensity in the presence of cholesterol has also been observed for IAPP protein (Christensen et al, 2021).…”

Amyloid β, Lipid Metabolism, Basal Cholinergic System, and Therapeutics in Alzheimer’s Disease

“…Cholesterol also contributes to membrane fluidity, promoting the packing of lipids, and is suggested to have a high affinity for Aβ, particularly by the fraction Aβ25–35 that could penetrate in the cholesterol monolayer [ 44 , 45 , 57 ]. Also, cholesterol participates in the amyloid pore’s formation, induced by different Aβ peptides (Aβ1–42, Aβ22–35, and Aβ25–35) [ 58 , 59 , 60 ]. In addition, multiple evidence has indicated that the amyloidogenic processing of AβPP occurs in specialized domains of the membrane known as lipid rafts [ 61 , 62 ].…”