Date Published: September 25, 2012
Publisher: Public Library of Science
Author(s): Xiaolin Zhou, Jie Xu, Damian Christopher Crowther. http://doi.org/10.1371/journal.pone.0046245
Accumulating experimental evidence support an enhancing effect of free cholesterol on amyloid-beta (Aβ) aggregation. To probe the mechanisms of cholesterol-mediated Aβ aggregation, we applied all-atom molecular dynamic simulations on Aβ42 peptides in presence of free cholesterol. Several control systems were also designed to examine the specificity of cholesterol-residue interactions, including mutation on aromatic residue, substitution of cholesterol with sphingomyelin (SM) and DPPC bilayer, and a mixing SM and cholesterol. Each system was performed 4 independent simulations, with a total time of 560 ns. It was found that cholesterol increased β-sheet formation by 4 folds, but the Phe19→Ser mutation on Aβ42 peptide totally eliminated cholesterol’s effect. A stable contact was recognized between the steroid group of cholesterol and the Benzyl group of Phe19. Interestingly, our simulation revealed a regular 1 ns time interval between the establishment of cholesterol-phenylalanine contact and consequent β-sheet formation, suggesting an important role of steroid-benzyl interaction in cholesterol-mediated aggregation. The presence of SM slightly increased β-sheet formation, but the mixture of cholesterol and SM had a strong induction effect. Also, the measurement of Phe19-lipid distance indicates that aromatic side chains of peptides prone to bind to cholesterol on the surface of the mixed micelle. In the DPPC system, polar chains were attracted to the surface of membrane, yielding moderate increase of β-sheet formation. These results shed light on the mechanism of cholesterol-mediated fibrillogenesis, and help to differentiate the effects of cholesterol and other lipids on β-sheet formation process.
Both epidemiological and experimental studies strongly implicate a role for cholesterol in the pathogenesis of Alzheimer’s disease (AD) . Experiments proved that cerebral amyloid-beta (Aβ) generation is cholesterol dependent , and drastically lowered Aβ levels were achieved by treating guinea pigs with simvastatin, a clinically used cholesterol-lowering drug . The exact mechanism about higher cholesterol level resulting in more amyloid aggregation is still unclear, but some hypotheses have been partially supported. Recent studies focused on the relationship between cholesterol level and amyloid precursor protein (APP) processing, trying to explain amyloidosis with elevated Aβ peptide generation . Evidence suggests that amyloid precursor protein (APP) processing may preferentially occur in the cholesterol-rich regions of membranes known as lipid rafts , and a harsh reduction of membrane cholesterol may affect APP processing . However, these experiments do not reveal a functional context explaining why the APP processing system responds in such a sensitive manner to cholesterol . In addition, multiple experiments demonstrated that the alternation of cholesterol level doesn’t affect the activities of α, β , or γ secretase , which are critical in APP processing. Thus, more experiments are needed to prove the causal relationship between cholesterol level and APP processing activity.
Using MD simulation method, we have studied the conformational transition of Aβ peptides in presence of cholesterol, SM and DPPC bilayer. The aromatic residue Phe19 was also mutated to examine the specificity of cholesterol interaction. Through these data, we are able to probe the mechanism of cholesterol-induced β-sheet formation.