Alzheimer’s disease is a neurodegenerative disorder associated with the aberrant aggregation of the amyloid-β peptide. Although increasing evidence implicates cholesterol in the pathogenesis of Alzheimer’s disease, the detailed mechanistic link between this lipid molecule and the disease process remains to be fully established. To address this problem, we adopt a kinetics-based strategy that reveals a specific catalytic role of cholesterol in the aggregation of Aβ42 (the 42-residue form of the amyloid-β peptide). More specifically, we demonstrate that lipid membranes containing cholesterol promote Aβ42 aggregation by enhancing its primary nucleation rate by up to 20-fold through a heterogeneous nucleation pathway. We further show that this process occurs as a result of cooperativity in the interaction of multiple cholesterol molecules with Aβ42. These results identify a specific microscopic pathway by which cholesterol dramatically enhances the onset of Aβ42 aggregation, thereby helping rationalize the link between Alzheimer’s disease and the impairment of cholesterol homeostasis.
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The authors acknowledge support from the Centre for Misfolding Diseases (J.H., S.C., T.C.T.M., M.M.J.B., F.S.R., M.S., J.R.K., C.M.D., T.P.J.K. and M.V.); the Agency for Science, Technology and Research, Singapore (S.C.); a Marie Skłodowska-Curie Actions — Individual Fellowship (C.G.); Peterhouse College, Cambridge (T.C.T.M.); the Swiss National Science Foundation (T.C.T.M., F.S.R.); the NIH-Oxford/Cambridge Scholars Program (M.M.J.B.); the Cambridge Commonwealth, European and International Trust (M.M.J.B.); the Knut & Alice Wallenberg Foundation (S.L., E.S.); the European Research Council (S.L.); the Swedish Research Council (S.L., E.S.) the Frances and Augustus Newman Foundation (T.P.J.K.); the UK Biotechnology and Biochemical Sciences Research Council (C.M.D. and M.V.); and the Wellcome Trust (C.M.D., T.P.J.K. and M.V.). This work was supported by the Intramural Research Program of the National Institute of Diabetes and Kidney Diseases, NIH.
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