Abstract
Amyloid β-protein (Aβ), which is known for its role in Alzheimer's disease (AD), is also involved in several physiological functions. Of the two predominant isoforms, Aβ40 and Aβ42, the latter is more aggregation-prone and more active in health and disease. In the brain, Aβ interacts with free lipids, which may affect its assembly pathways. Here, thioflavin T (ThT) fluorescence spectroscopy is combined with molecular dynamics (MD) to investigate Aβ40 and Aβ42 co-assembly with free dimyristoylphosphatidylcholine (DMPC) and DMPC/cholesterol (CHOL) lipids. ThT measurements at several protein-to-lipid (PL) ratios show isoform- and lipid composition-dependent kinetics of Aβ fibril formation with clear isoform-dependent lipid effects at a PL ratio of 1:5. Early co-assembly stages of six Aβ40/Aβ42 with DMPC and DMPC/CHOL lipids at this PL ratio are then examined by MD. MD results indicate that lipids alter the secondary structure more and interact more avidly with Aβ40 than with Aβ42. In turn, Aβ40 increases the planar order of lipid bicelles more than Aβ42. Unlike Aβ40, Aβ42 decreases the nematic order of CHOL. In DMPC/CHOL lipids, Aβ42 but not Aβ40 exhibits two Aβ-lipid interaction modes associated with mutually exclusive Aβ42-lipid and Aβ42-Aβ42 interactions. Our MD findings provide a plausible explanation for an experimentally observed increase in the lag time for Aβ40 fibril formation in DMPC lipids and even more so in DMPC/CHOL lipids that contrasts with much smaller effects of lipids on Aβ42 fibril formation and offer additional atomistic-level insights into Aβ co-assembly with lipids amenable to experimental testing.