Beta-sheet structured beta-amyloid(1-40) perturbs phosphatidylcholine model membranes

de Planque, M.R.R., Raussens, V., Antoranz Contera, S., Rijkers, D.T.S., Liskamp, R.M.J., Ruysschaert, J-M., Ryan, J.F., Separovic, F. and Watts, A. (2007) Beta-sheet structured beta-amyloid(1-40) perturbs phosphatidylcholine model membranes. Journal of Molecular Biology, 368 (4), 982-997. (doi:10.1016/j.jmb.2007.02.063).

Abstract

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-? peptides A?40 and A?42. 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 A?. Primarily unstructured A? has been shown to undergo a membrane-induced conformational change to either primarily ?-structure or helical structure, depending, among other factors, on the model membrane composition. Association of A? renders lipid bilayers permeable to ions but there is dispute whether this is due to the formation of discrete transmembrane ion channels of A? peptides, or to a non-specific perturbation of bilayer integrity by lipid head group-associated A?. Here, we have attempted incorporation of A? in the hydrophobic core of zwitterionic bilayers, the most simple model membrane system, by preparing proteoliposomes by hydration of a mixed film of A? peptides and phosphatidylcholine (PC) lipids. Despite the use of a solvent mixture in which A?40 and A?42 are almost entirely helical, the A? analogs were ?-structured in the resulting vesicle dispersions. When A?40-containing vesicles were fused into a zwitterionic planar bilayer, the typical irregular “single channel-like” conductance of A? was observed. The maximum conductance increased with additional vesicle fusion, while still exhibiting single channel-like behavior. Supported bilayers formed from A?40/PC vesicles did not exhibit any channel-like topological features, but the bilayer destabilized in time. A?40 was present primarily as ?-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 A?40 assemblies.

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Contributors

Author: M.R.R. de Planque

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