Cholesterol catalyses Aβ42 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-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.

β‐Amyloid aggregation and heterogeneous nucleation

“…More recently, DMPC:cholesterol vesicles were shown to accelerate Aβ(1–42) aggregation by accelerating the rate of Aβ(1–42) primary nucleation by up to 20‐fold . Through a detailed analysis of kinetics, this effect was shown, in particular, for the heterogeneous nucleation of Aβ(1–42) oligomers .…”

“…More recently, DMPC:cholesterol vesicles were shown to accelerate Aβ(1-42) aggregation by accelerating the rate of Aβ(1-42) primary nucleation by up to 20-fold. 77 Through a detailed analysis of kinetics, this effect was shown, in particular, for the heterogeneous nucleation of Aβ(1-42) oligomers. 77 Furthermore, because this interaction is a cooperative one, in which multiple cholesterol molecules interact with Aβ(1-42), these results could help rationalize the association between aggregation of Aβ(1-42) and impaired cholesterol metabolism.…”

Far from Inert: Membrane Lipids Possess Intrinsic Reactivity That Has Consequences for Cell Biology

“…Appealing features of this shorter pathway are its brevity and the retention of the Aβ peptide in the membrane. The timescales for a lipidation‐driven nucleation are reasonable, as even in systems with accelerated nucleation, the nucleation half times are greater than 1 h, putting them on the timescale that lipidation of melittin begins to be observable …”

Cholesterol: A Key in the Pathogenesis of Alzheimer's Disease

“…[14] They used ak inetics-based methodology based on thioflavin-T (ThT)-based kinetic measurements to quantitativelya nalyze the direct effects of cholesterol on Ab42 aggregation (Scheme 1). [14] They used ak inetics-based methodology based on thioflavin-T (ThT)-based kinetic measurements to quantitativelya nalyze the direct effects of cholesterol on Ab42 aggregation (Scheme 1).…”

“…[14] They used ak inetics-based methodology based on thioflavin-T (ThT)-based kinetic measurements to quantitativelya nalyze the direct effects of cholesterol on Ab42 aggregation (Scheme 1). [14] This strategy enabled them to show the accumulationo fA b42 as af unctiono fs urface-catalyzed secondary nucleation.T hey observed that the fibril surfaces act as catalytic sites for the formation of toxic Ab42 oligomers, in good agreement with the earlier report by Knowles et al [2] The oligomers grow further to fibrils, thusp romoting the formation of additional toxic speciesi nahighly effective catalytic cycle. They also explored the effects of intrinsic and extrinsic factors such as molecular chaperones and antibodies on the rates of individual microscopics teps in the aggregationp rocess of Ab42.…”