1-palmitoyl-2-oleoylglycero-3-phosphoglycerol and Alzheimer-Disease

Interaction of p3 (Aβ(17-42)) peptides with cell membranes is crucial for the understanding of amyloid toxicity associated with Alzheimer's disease (AD). Such p3-membrane interactions are considered to induce the disruption of membrane permeability and integrity, but the exact mechanisms of how p3 aggregates, particularly small p3 oligomers, induce receptor-independent membrane disruption are not yet completely understood. Here, we investigate the adsorption, orientation, and surface interaction of the p3 pentamer with lipid bilayers composed of both pure zwitterionic POPC (palmitoyl-oleoyl-phosphatidylcholine) and mixed anionic POPC-POPG (palmitoyl-oleoyl-phosphatidylglycerol) (3 : 1) lipids using explicit-solvent molecular dynamics (MD) simulations. MD simulation results show that the p3 pentamer has much stronger interactions with mixed POPC-POPG lipids than pure POPC lipids, consistent with experimental observation that Aβ adsorption and fibrillation are enhanced on anionic lipid bilayers. Although electrostatic interactions are main attractive forces to drive the p3 pentamer to adsorb on the bilayer surface, the adsorption of the p3 pentamer on the lipid bilayer with C-terminal β-strands facing toward the bilayer surface is a net outcome of different competitions between p3 peptides-lipid bilayer and ions-p3-bilayer interactions. More importantly, Ca(2+) ions are found to form ionic bridges to associate negatively charged residues of p3 with anionic headgroups of the lipid bilayer, resulting in Aβ-Ca(2+)-PO4(-) complexes. Intensive Ca(2+) bound to the lipid bilayer and Ca(2+) ionic bridges may lead to Ca(2+) hemostasis responsible for neuronal dysfunction and death. This work provides insights into the mutual structure, dynamics, and interactions of both Aβ peptides and lipid bilayers at the atomic level, which expand our understanding of the complex behavior of amyloid-induced membrane disruption.

Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid beta-Peptides; Calcium; Humans; Lipid Bilayers; Molecular Dynamics Simulation; Molecular Sequence Data; Peptide Fragments; Phosphatidylcholines; Phosphatidylglycerols; Protein Structure, Secondary

The etiology of Alzheimer's disease is thought to be linked to interactions between amyloid-β (Aβ) and neural cell membranes, causing membrane disruption and increased ion conductance. The effects of Aβ on lipid behavior have been characterized experimentally, but structural and causal details are lacking. We used atomistic molecular dynamics simulations totaling over 6 μs in simulation time to investigate the behavior of Aβ(42) in zwitterionic and anionic lipid bilayers. We simulated transmembrane β-sheets (monomer and tetramer) resulting from a global optimization study and a helical structure obtained from an NMR study. In all simulations Aβ(42) remained embedded in the bilayer. It was found that the surface charge and the lipid tail type are determinants for transmembrane stability of Aβ(42) with zwitterionic surfaces and unsaturated lipids promoting stability. From the considered structures, the β-sheet tetramer is most stable as a result of interpeptide interactions. We performed an in-depth analysis of the translocation of water in the Aβ(42)-bilayer systems. We observed that this process is generally fast (within a few nanoseconds) yet generally slower than in the peptide-free bilayers. It is mainly governed by the lipid type, simulation temperature and Aβ(42) conformation. The rate limiting step is the permeation through the hydrophobic core, where interactions between Aβ(42) and permeating H(2)O molecules slow the translocation process. The β-sheet tetramer allows more water molecules to pass through the bilayer compared to monomeric Aβ, allowing us to conclude that the experimentally observed permeabilization of membranes must be due to membrane-bound Aβ oligomers, and not monomers.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Algorithms; Alzheimer Disease; Amyloid beta-Peptides; Cell Membrane; Computer Simulation; Humans; Hydrogen-Ion Concentration; Ions; Lipid Bilayers; Lipids; Magnetic Resonance Spectroscopy; Peptides; Phosphatidylcholines; Phosphatidylglycerols; Protein Structure, Secondary; Temperature; Water

Amyloid beta-peptides (A beta) are centrally involved in the pathogenesis of Alzheimer's disease. Using secretory phospholipase A2 (PLA2) from porcine pancreas as a model and in the presence of a limiting Ca2+ concentration of approximately 50 nM, the synthetic peptide A beta 1-42 activates the hydrolysis of the pyrene-labeled acidic phospholipid analog 1-palmitoyl-2-[(pyren-1-yl)]hexanoyl-sn-glycero-3-phosphoglycerol (PPHPG) maximally 2.3-fold, whereas an inhibition of PLA2 action by 50% on the corresponding phosphatidylcholine derivative (PPHPC) was observed. The above effects were evident at 0.24 nM A beta 1-42 corresponding to A beta 1-42:phospholipid and A beta 1-42:PLA2 molar ratios of 1:10 650 and 1:7.6, respectively. The presence of 10 mol % 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) in PPHPC reversed the inhibitory effect of A beta 1-42 peptide and for these vesicles the hydrolytic activity of PLA2 toward the fluorescent phosphatidylcholine was enhanced approximately 1.8-fold by A beta 1-42. In contrast, inclusion of 10 mol % POPG into PPHPG did not influence either the hydrolytic rate toward the latter lipid or the activating effect of A beta 1-42. Ca2+ concentrations exceeding 15 microM abolished the enhancing effect of A beta 1-42 on the hydrolysis of PPHPG whereas a slight activation of PPHPC hydrolysis now became evident. With limiting [Ca2+] preaggregated A beta 1-42 enhanced the hydrolysis of both PPHPG as well as PPHPC but the peptide concentrations required were higher by 3-4 orders of magnitude. The synthetic peptide A beta 25-35 corresponding to the hydrophobic membrane-spanning segment of the beta amyloid precursor protein activated PLA2 when using PPHPG as a substrate; however, compared to A beta 1-42 the extent of activation was less (approximately 2-fold) and required higher (1 nM) peptide. A beta 25-35 did not affect the hydrolysis of the phosphatidylcholine derivative. The hydrophilic peptide A beta 1-28 had no effect on PLA2-catalyzed hydrolysis of either PPHPG or PPHPC under the conditions used in the present study. Interestingly, the above activating effects of A beta 1-42 and A beta 25-35 on PLA2-catalyzed hydrolysis of the acidic phospholipid substrate parallel their toxicity on cultured neurons whereas A beta 1-28 had no influence either on cultured cells or on PLA2 activity.

Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid beta-Peptides; Animals; Calcium; Edetic Acid; Enzyme Activation; Humans; Hydrolysis; Kinetics; Molecular Sequence Data; Pancreas; Peptide Fragments; Phosphatidylglycerols; Phospholipases A; Phospholipases A2; Phospholipids; Swine