Amyloid β interaction with membranes: Removal of cholesterol from the membranes to catalyze aggregation and amyloid pathology

The interplay between the cholesterol metabolism and assembly of Aβ42 (the 42-residue form of the amyloid-β peptide) peptides in pathological aggregates is considered as one of the major molecular mechanisms in development of Alzheimer's disease (AD). Numerous in vitro studies led to the finding that the high cholesterol levels in membranes accelerate the production of Aβ aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of Aβ aggregates above the membrane remain unknown. We addressed this problem by combining different AFM modalities, including imaging and force spectroscopy, with fluorescence spectroscopy. Our combined studies revealed that Aβ42 was capable of removing cholesterol from the membrane. Importantly, physiologically low concentrations of Aβ42 demonstrate such ability of monomeric Aβ42. Extracted cholesterol interacts with Aβ42 and accelerates its on-membrane aggregation. We propose a model of interaction of Aβ42 with membranes based on the ability of Aβ42 to extract cholesterol, which explains several AD associated observations related to cholesterol interplay with Aβ42 aggregation resulting in the AD onset and progression.