beta-Sheet structured beta-amyloid(1-40) perturbs phosphatidylcholine model membranes.
The disruption of intracellular calcium homeostasis plays a central role in the pathology of Alzheimer's disease, which is also characterized by accumulation of the amyloid-beta peptides Abeta40 and Abeta42. These amphipathic peptides may become associated with neuronal membranes and affect their barrier function, resulting in the loss of calcium homeostasis. This suggestion has been extensively investigated by exposing protein-free model membranes, either vesicles or planar bilayers, to soluble Abeta. Primarily unstructured Abeta has been shown to undergo a membrane-induced conformational change to either primarily beta-structure or helical structure, depending, among other factors, on the model membrane composition. Association of Abeta renders lipid bilayers permeable to ions but there is dispute whether this is due to the formation of discrete transmembrane ion channels of Abeta peptides, or to a non-specific perturbation of bilayer integrity by lipid head group-associated Abeta. Here, we have attempted incorporation of Abeta in the hydrophobic core of zwitterionic bilayers, the most simple model membrane system, by preparing proteoliposomes by hydration of a mixed film of Abeta peptides and phosphatidylcholine (PC) lipids. Despite the use of a solvent mixture in which Abeta40 and Abeta42 are almost entirely helical, the Abeta analogs were beta-structured in the resulting vesicle dispersions. When Abeta40-containing vesicles were fused into a zwitterionic planar bilayer, the typical irregular "single channel-like" conductance of Abeta was observed. The maximum conductance increased with additional vesicle fusion, while still exhibiting single channel-like behavior. Supported bilayers formed from Abeta40/PC vesicles did not exhibit any channel-like topological features, but the bilayer destabilized in time. Abeta40 was present primarily as beta-sheets in supported multilayers formed from the same vesicles. The combined observations argue for a non-specific perturbation of zwitterionic bilayers by surface association of small amphipathic Abeta40 assemblies.
de Planque
Maurits R R
MR
Biomembrane Structure Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. m.deplanque1@physics.ox.ac.uk
Raussens
Vincent
V
Contera
Sonia Antoranz
SA
Rijkers
Dirk T S
DT
Liskamp
Rob M J
RM
Ruysschaert
Jean-Marie
JM
Ryan
John F
JF
Separovic
Frances
F
Watts
Anthony
A
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D018625:Microscopy, Atomic Force; D010446:Peptide Fragments / Q000737:chemistry*; D010713:Phosphatidylcholines / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared
D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D008081:Liposomes; D010446:Peptide Fragments; D010713:Phosphatidylcholines; C078592:amyloid beta-protein (1-40)