amyloid-beta-peptides and dimyristoylphosphatidylglycerol

The interaction between lipid bilayers and Amyloid β peptide (Aβ) plays a critical role in proliferation of Alzheimer's disease (AD). AD is expected to affect one in every 85 humans by 2050, and therefore, deciphering the interplay of Aβ and lipid bilayers at the molecular level is of profound importance. In this work, we applied an array of neutron scattering methods to study the structure and dynamics of Aβ(1-40) interacting 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) bilayers. In the structural investigations of lipid bilayer's response to Aβ binding, Small Angle Neutron Scattering and Neutron Membrane Diffraction revealed that the Aβ anchors firmly to the highly charged DMPG bilayers in the interfacial region between water and hydrocarbon chain, and it doesn't penetrate deeply into the bilayer. This association mode is substantiated by the dynamics studies with high resolution Quasi-Elastic Neutron Scattering experiments, showing that the addition of Aβ mainly affects the slower lateral motion of lipid molecules, especially in the fluid phase, but not the faster internal motion. The results revealed that Aβ associates with the highly charged membrane in surface with limited impact on the structure, but the altered membrane dynamics could have more influence on other membrane processes.

Topics: Amyloid beta-Peptides; Humans; Lipid Bilayers; Neutron Diffraction; Peptide Fragments; Phosphatidylglycerols; Scattering, Small Angle

The β-amyloid (Aβ) peptide is derived from the transmembrane (TM) helix of the amyloid precursor protein (APP) and has been shown to interact with membrane surfaces. To understand better the role of peptide-membrane interactions in cell death and ultimately in Alzheimer's disease, a better understanding of how membrane characteristics affect the binding, solvation, and secondary structure of Aβ is needed. Employing a combination of circular dichroism and deep-UV resonance Raman spectroscopies, Aβ(25-40) was found to fold spontaneously upon association with anionic lipid bilayers. The hydrophobic portion of the disease-related Aβ(1-40) peptide, Aβ(25-40), has often been used as a model for how its legacy TM region may behave structurally in aqueous solvents and during membrane encounters. The structure of the membrane-associated Aβ(25-40) peptide was found to depend on both the hydrophobic thickness of the bilayer and the duration of incubation. Similarly, the disease-related Aβ(1-40) peptide also spontaneously associates with anionic liposomes, where it initially adopts mixtures of disordered and helical structures. The partially disordered helical structures then convert to β-sheet structures over longer time frames. β-Sheet structure is formed prior to helical unwinding, implying a model in which β-sheet structure, formed initially from disordered regions, prompts the unwinding and destabilization of membrane-stabilized helical structure. A model is proposed to describe the mechanism of escape of Aβ(1-40) from the membrane surfaces following its formation by cleavage of APP within the membrane.

Topics: Amyloid beta-Peptides; Circular Dichroism; Dimyristoylphosphatidylcholine; Hydrophobic and Hydrophilic Interactions; Lipid Bilayers; Models, Chemical; Peptide Fragments; Peptides; Phosphatidylglycerols; Protein Folding; Protein Structure, Secondary; Solvents; Spectrum Analysis, Raman

The 39-42 amino acid long, amphipathic amyloid-beta peptide (Abeta) is one of the key components involved in Alzheimer's disease (AD). In the neuropathology of AD, Abeta presumably exerts its neurotoxic action via interactions with neuronal membranes. In our studies a combination of 31P MAS NMR (magic angle spinning nuclear magnetic resonance) and CD (circular dichroism) spectroscopy suggest fundamental differences in the functional organization of supramolecular Abeta(1-40) membrane assemblies for two different scenarios with potential implication in AD: Abeta peptide can either be firmly anchored in a membrane upon proteolytic cleavage, thereby being prevented against release and aggregation, or it can have fundamentally adverse effects when bound to membrane surfaces by undergoing accelerated aggregation, causing neuronal apoptotic cell death. Acidic lipids can prevent release of membrane inserted Abeta(1-40) by stabilizing its hydrophobic transmembrane C-terminal part (residue 29-40) in an alpha-helical conformation via an electrostatic anchor between its basic Lys28 residue and the negatively charged membrane interface. However, if Abeta(1-40) is released as a soluble monomer, charged membranes act as two-dimensional aggregation-templates where an increasing amount of charged lipids (possible pathological degradation products) causes a dramatic accumulation of surface-associated Abeta(1-40) peptide followed by accelerated aggregation into toxic structures. These results suggest that two different molecular mechanisms of peptide-membrane assemblies are involved in Abeta's pathophysiology with the finely balanced type of Abeta-lipid interactions against release of Abeta from neuronal membranes being overcompensated by an Abeta-membrane assembly which causes toxic beta-structured aggregates in AD. Therefore, pathological interactions of Abeta peptide with neuronal membranes might not only depend on the oligomerization state of the peptide, but also the type and nature of the supramolecular Abeta-membrane assemblies inherited from Abeta's origin.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Circular Dichroism; Dimyristoylphosphatidylcholine; Kinetics; Liposomes; Magnetic Resonance Spectroscopy; Membrane Lipids; Models, Biological; Peptide Fragments; Phosphatidylglycerols; Protein Binding; Protein Structure, Quaternary; Protein Structure, Secondary