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

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

alzheimer's disease, amyloid-? peptide, membranes, phosphatidylcholine, lipid bilayer perturbation
0022-2836
982-997
de Planque, M.R.R.
a1d33d13-f516-44fb-8d2c-c51d18bc21ba
Raussens, V.
5545580f-92c6-40df-9d20-f64c73d58ef7
Antoranz Contera, S.
210f5921-5a7e-4289-a11a-9f5a09a1a92a
Rijkers, D.T.S.
7d6831d3-86b5-4107-ad75-6a234ac56543
Liskamp, R.M.J.
c101a850-1064-404b-ae73-8d0d31cd079d
Ruysschaert, J-M.
f7a55807-6756-478a-8148-5fb0627d54ab
Ryan, J.F.
2c388137-99a9-4d73-b237-31a5eaa7f692
Separovic, F.
6c67fe78-52e0-4786-a89a-e618e6c0e992
Watts, A.
9d52521b-918a-4f29-aaa7-c2c3f386696f
de Planque, M.R.R.
a1d33d13-f516-44fb-8d2c-c51d18bc21ba
Raussens, V.
5545580f-92c6-40df-9d20-f64c73d58ef7
Antoranz Contera, S.
210f5921-5a7e-4289-a11a-9f5a09a1a92a
Rijkers, D.T.S.
7d6831d3-86b5-4107-ad75-6a234ac56543
Liskamp, R.M.J.
c101a850-1064-404b-ae73-8d0d31cd079d
Ruysschaert, J-M.
f7a55807-6756-478a-8148-5fb0627d54ab
Ryan, J.F.
2c388137-99a9-4d73-b237-31a5eaa7f692
Separovic, F.
6c67fe78-52e0-4786-a89a-e618e6c0e992
Watts, A.
9d52521b-918a-4f29-aaa7-c2c3f386696f

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).

Record type: Article

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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More information

Published date: 11 May 2007
Keywords: alzheimer's disease, amyloid-? peptide, membranes, phosphatidylcholine, lipid bilayer perturbation

Identifiers

Local EPrints ID: 48602
URI: https://eprints.soton.ac.uk/id/eprint/48602
ISSN: 0022-2836
PURE UUID: 8f1bd720-b739-48ac-82c1-3dfaef5b1de8
ORCID for M.R.R. de Planque: ORCID iD orcid.org/0000-0002-8787-0513

Catalogue record

Date deposited: 03 Oct 2007
Last modified: 14 Mar 2019 01:39

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Contributors

Author: V. Raussens
Author: S. Antoranz Contera
Author: D.T.S. Rijkers
Author: R.M.J. Liskamp
Author: J-M. Ruysschaert
Author: J.F. Ryan
Author: F. Separovic
Author: A. Watts

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