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Open Access Research article

Autoinsertion of soluble oligomers of Alzheimer's Aβ(1–42) peptide into cholesterol-containing membranes is accompanied by relocation of the sterol towards the bilayer surface

Richard H Ashley1*, Thad A Harroun26, Thomas Hauss3, Kieran C Breen47 and Jeremy P Bradshaw5

Author Affiliations

1 Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH8 9XD, UK

2 Canadian Neutron Beam Centre, Chalk River Laboratories, Chalk River, Ontario K0J 1J0, Canada

3 Abteilung SF2/Biophysik, Hahn-Meitner-Institut, D-14109 Berlin, Germany, and Physical Biochemistry, Dept. of Chemistry, DarmstadtUniversity of Technology, Petersenstrasse 22, D-64287 Darmstadt, Germany

4 Department of Psychiatry, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK

5 Veterinary Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH25 9RG, UK

6 Department of Physics, Brock University, St. Catharines, Ontario L2S 3A1, Canada

7 The Parkinson's Disease Society of the United Kingdom, London SW1V 1EJ, UK

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BMC Structural Biology 2006, 6:21  doi:10.1186/1472-6807-6-21

Published: 19 October 2006

Abstract

Background

Soluble Alzheimer's Aβ oligomers autoinsert into neuronal cell membranes, contributing to the pathology of Alzheimer's Disease (AD), and elevated serum cholesterol is a risk factor for AD, but the reason is unknown. We investigated potential connections between these two observations at the membrane level by testing the hypothesis that Aβ(1–42) relocates membrane cholesterol.

Results

Oligomers of Aβ(1–42), but not the monomeric peptide, inserted into cholesterol-containing phosphatidylcholine monolayers with an anomalously low molecular insertion area, suggesting concurrent lipid rearrangement. Membrane neutron diffraction, including isomorphous replacement of specific lipid hydrogens with highly-scattering deuterium, showed that Aβ(1–42) insertion was accompanied by outward displacement of membrane cholesterol, towards the polar surfaces of the bilayer. Changes in the generalised polarisation of laurdan confirmed that the structural changes were associated with a functional alteration in membrane lipid order.

Conclusion

Cholesterol is known to regulate membrane lipid order, and this can affect a wide range of membrane mechanisms, including intercellular signalling. Previously unrecognised Aβ-dependent rearrangement of the membrane sterol could have an important role in AD.