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 ∼10 nm diameter cholesterol-PEG 600 micelles to amyloid-β1-42 (Aβ1-42) 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 °C the cholesterol-PEG micelles bound periodically to Aβ1-42 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 Aβ1-42 fibrils, generated in the presence of cholesterol microcrystals or hydrogen peroxide (1 mM), bound cholesterol-PEG micelles with no immediately apparent regularity and without creating a smooth coating. The differing capacities of the Aβ1-42 protofibrils and mature double helical fibrils to bind cholesterol-PEG 600 may indicate differences in the accessibility of the micellar cholesterol to the purported Aβ17-21 hydrophobic cholesterol-binding motif on the fibril surfaces.