Internal medicine

Cooperativity

Organic chemistry

Pathogenesis

Membrane

Nucleation

Biology

Biophysics

Inorganic chemistry

Chemistry

Amyloid (mycology)

Cholesterol

Peptide

Lipid bilayer

Biochemistry

Medicine

Nature Chemistry

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. Cholesterol embedded in lipid membranes strongly promotes the aggregation of Aβ42 that is associated with Alzheimer's disease. Now, a kinetic analysis has shown that the mechanism of action responsible for this effect involves the introduction of a heterogeneous nucleation pathway that enhances the primary nucleation rate of Aβ42 aggregation by up to 20-fold.

Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes