Interaction between Alzheimer's Aβ(25–35) peptide and phospholipid bilayers: The role of cholesterol

Abstract

There is mounting evidence that the lipid matrix of neuronal cell membranes plays an important role in the accumulation of beta-amyloid peptides into senile plaques, one of the hallmarks of Alzheimer's disease (AD). With the aim to clarify the molecular basis of the interaction between amyloid peptides and cellular membranes, we investigated the interaction between a cytotoxic fragment of Abeta(1-42), i.e., Abeta(25-35), and phospholipid bilayer membranes. These systems were studied by Electron Paramagnetic Resonance (EPR) spectroscopy, using phospholipids spin-labeled on the acyl chain. The effect of inclusion of charged phospholipids or/and cholesterol in the bilayer composition was considered in relation to the peptide/membrane interaction. The results show that Abeta(25-35) inserts in bilayers formed by the zwitterionic phospholipid dilauroyl phosphatidylcholine (DLPC), positioning between the outer part of the hydrophobic core and the external hydrophilic layer. This process is not significantly influenced by the inclusion of the anionic phospholipid phosphatidylglycerol (DLPG) in the bilayer, indicating the peptide insertion to be driven by hydrophobic rather than electrostatic interactions. Cholesterol plays a fundamental role in regulating the peptide/membrane association, inducing a membrane transition from a fluid-disordered to a fluid-ordered phase. At low cholesterol content, in the fluid-disordered phase, the insertion of the peptide in the membrane causes a displacement of cholesterol towards the more external part of the membrane. The crowding of cholesterol enhances its rigidifying effect on this region of the bilayer. Finally, the cholesterol-rich fluid-ordered membrane looses the ability to include Abeta(25-35).

Embedding Aβ42 in Heterogeneous Membranes Depends on Cholesterol Asymmetries

“…These findings where confirmed for the same peptide fragment, via electron paramagnetic resonance spectroscopy on spin-labeled phospholipid acyl tails, which showed that cholesterol, and not leaflet charge, affects the ability of Ab fragments to insert (50). Our results are fully consistent with these experimental studies in that the C-terminus of Ab does embed into the membrane, but the N-terminus is exposed to the extracellular space.…”

Investigating the Neuroprotective Effects of Turmeric Extract: Structural Interactions of β-Amyloid Peptide with Single Curcuminoids

“…This evidence indicates that A β (25–35) is inserted in the bilayer positioning between the outer part of the hydrophobic core and the external hydrophilic layer. A similar solubilization site was already observed in other lipid systems5863. When A β (25–35) is added to the lipid bilayers in the presence of curcumin or its analogues, the 5-PCSL spectrum is much less affected, and in some cases, no variation is observed (see Table 2SI).…”

Cholesterol Promotes the Interaction of Alzheimer β-Amyloid Monomer with Lipid Bilayer

“…Aβ 1-40 is a more abundant species, whereas Aβ 1-42 is a more neurontoxic species. Recent studies [2][3][4][5] have proposed that the mechanism of Aβ-mediated toxicity is correlated with its ability to disrupt the integrity and permeability of cell membrane. Under different experimental conditions, Aβ peptides can either penetrate into membrane to form ion channels/pores 6,7 or associate with the membrane surface to induce membrane thinning.…”