Cholesterol catalyses Aß42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes.

ABSTRACT

Alzheimer's disease is a neurodegenerative disorder associated with the aberrant aggregation of the amyloid-ß 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 Aß42 (the 42-residue form of the amyloid-ß peptide). More specifically, we demonstrate that lipid membranes containing cholesterol promote Aß42 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 Aß42. These results identify a specific microscopic pathway by which cholesterol dramatically enhances the onset of Aß42 aggregation, thereby helping rationalize the link between Alzheimer's disease and the impairment of cholesterol homeostasis.