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

Background: Soluble Alzheimer's A beta 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 A beta(1-42) relocates membrane cholesterol. Results: Oligomers of A beta(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 A beta(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 A beta-dependent rearrangement of the membrane sterol could have an important role in AD.