Cholesterol binding to amyloid-β fibrils: A TEM study

There is increasing interest in the role of brain cholesterol in Alzheimer's disease and the contribution of cholesterol to the formation of amyloid plaques. This paper presents a TEM study showing the binding of soluble similar to 10 nm diameter cholesterol-PEG 600 micelles to amyloid-beta(1-42) (A beta(1-42)) fibrils formed either in the presence of this cholesterol derivative or to preformed fibrils generated under four different fibrillogenesis conditions. Specimens negatively stained with uranyl acetate revealed that during 24 h fibrillogenesis at 37 degrees C the cholesterol-PEG micelles bound periodically to A beta(1-42) protofibrils and apparently also formed a thin smooth unbroken coating on mature double helical fibrils. Preformed protofibrils, generated in water alone or in the presence of 0.1 mM cupric sulphate, also exhibited periodic binding of cholesterol-PEG micelles, indicating the inherently helical nature of the protofibril. Double helical mature A beta(1-42) fibrils, generated in the presence of cholesterol microcrystals or hydrogen peroxide (I mM), bound cholesterol-PEG micelles with no immediately apparent regularity and without creating a smooth coating. The differing capacities of the A beta(1-42) protofibrils and mature double helical fibrils to bind cholesterol-PEG 600 may indicate differences in the accessibility of the micellar cholesterol to the purported A beta(17-21) hydrophobic cholesterol-binding motif on the fibril surfaces. (C) 2008 Elsevier Ltd. All rights reserved.