Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide. A hallmark of AD pathogenesis is the aggregation of amyloid-β (Aβ) peptides, whose interactions with neuronal membranes are thought to compromise membrane integrity and impair neuronal function. Cholesterol, a major component of neuronal membranes, has been implicated in modulating Aβ-membrane interactions. However, its role in the development of AD remains controversial, with studies reporting both protective and detrimental effects. To investigate the role of cholesterol in Aβ-membrane interactions, we employed Gaussian accelerated molecular dynamics (GaMD) simulations, an enhanced sampling technique, to study the interactions of 42-residue Aβ monomers (Aβ42) with the membrane. We derived the initial Aβ structure from an AlphaFold2 prediction of the C55 monomer, with residues 43–55 removed to reflect the Aβ42 peptide produced following cleavage by the membrane protein γ-secretase. We constructed bilayers composed of POPC, DPPC, or sphingomyelin (SM) with cholesterol concentrations of 0%, 10%, 18%, and 40%. The Aβ peptide was embedded in each system with an orientation and depth matching the experimentally resolved model of C99-γ-secretase complex (PDB ID: 8X53). Our simulations revealed that across all lipid types, increasing cholesterol concentration promoted deeper insertion of Aβ into the membrane. In bilayers with 0% or 10% cholesterol, the peptide migrated toward the surface of the upper leaflet and partially exited the bilayer, whereas in membranes with 18% or 40% cholesterol, Aβ inserted further into the membrane. Membranes with higher cholesterol concentrations also exhibited increased lipid order parameters and reduced lipid tilt angles, indicating that elevated cholesterol level induces membrane rigidification. This rigidification, in turn, stabilized Aβ insertion. Together, our findings offer mechanistic insight into how membrane composition and cholesterol levels influence Aβ behavior and contribute to potential AD progression.
Qian et al. (Sun,) studied this question.