Molecular Dynamics Simulations Reveal the Protective Role of Cholesterol in β-Amyloid Protein-Induced Membrane Disruptions in Neuronal Membrane Mimics

Abstract

Interactions of beta-amyloid (Aβ) peptides with neuronal membranes have been associated with the pathogenesis of Alzheimer’s disease, however the molecular details remain unclear. We used atomistic molecular dynamics simulations to study the interactions of Aβ40 and Aβ42 with model neuronal membranes. The differences between cholesterol-enriched and -depleted lipid domains were investigated by use of model phosphatidylcholine lipid bilayers with and without 40 mole % cholesterol. Sixteen independent 200 ns-simulation replicates were investigated. The surface area per lipid, bilayer thickness, water permeability barrier, and lipid order parameter, which are sensitive indicators of membrane disruption, were significantly altered by the inserted state of the protein. We conclude that cholesterol protects Aβ-induced membrane disruption and inhibits beta-sheet formation of Aβ on the lipid bilayer. The latter could represent a 2D seeding-template for the formation of toxic oligomeric Aβ in the pathogenesis of Alzheimer’s disease.

Interactions of Lipid Membranes with Fibrillar Protein Aggregates

“…Hence, the ability of fibrils to modify physical properties of the interfacial membrane region can be hampered by cholesterol. This observation is in good agreement with numerous studies suggesting that cholesterol can prevent membrane disruption by the aggregated proteins (Sponne et al 2004;Cecchi et al 2005;Qiu et al 2011). In particular, cholesterol was demonstrated to protect primary cortical neurons from neurotoxic effects of soluble oligomeric Aβ /W@8 in the model membranes comprised of PC, PC/CL (9:1, mol:mol) and PC/Chol (7:3, mol:mol).…”

Scaling and alpha-helix regulation of protein relaxation in a lipid bilayer

“…The longer time-scale behavior seen in these simulations, including membrane disruption and the effect of CHOL has been previously published. 6 The starting structure was Aβ 40 or Aβ 42 half-embedded into the extracellular leaflet of a lipid bilayer. Initial structures of lipid bilayers were constructed by tiling four identical periodic images of equilibrated PC and PC/CHOL bilayers from previous work.…”

“…5 The initial structure of Aβ 42 was created from that of Aβ 40 by appending Ile41 and Ala42 to the C-terminus and relaxed in water through short MD simulations. 6 For the A and B series, two PC lipids in the extracellular leaflet were removed from the PC bilayer to provide an insertion point. One protein molecule, Aβ 40 for the A series or Aβ 42 for the B series, was then inserted into the lipid layer void.…”

“…Importantly, this force field combination allowed consistent parameterization of all the components of interest: PC, CHOL, peptide, and water. 6,31,32 Implications of using GROMOS87 and the Berger parameters are outlined in Sec. IV.…”

“…4 The distinctive lipid insertion domain (LID) of Aβ is a short transmembrane (TM) segment containing 11-13 non-polar residues bounded, at physiological pH, by a charged lysine and the charged C-terminus. 5,6 The LID contains the essential elements of protein membrane translocation: (i) a charged terminus that can bind to a lipid target on the trans-side of the membrane, (ii) a charged residue that can anchor the protein by binding to the cytosolic side of the membrane, and (iii) a loosely folded insertion structure. [7][8][9] We find that the negatively charged, deprotonated C-terminus, Ala40 or Val42, can descend and anchor to the phosphate of the polar headgroup region of the cytofacial leaflet of the lipid bilayer.…”