Amyloid β interaction with membranes: Removal of cholesterol from the membranes to catalyze aggregation and amyloid pathology
Baral, R.; van Deventer, R.; Lyubchenko, Y. L.
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The interplay between the cholesterol metabolism and assembly of A{beta}42 (the 42- residue form of the amyloid-{beta} peptide) peptides in pathological aggregates is considered as one of the major molecular mechanisms in development of Alzheimers disease (AD). Numerous in vitro studies led to the finding that the high cholesterol levels in membranes accelerate the production of A{beta} aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of A{beta} 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 A{beta}42 was capable of removing cholesterol from the membrane. Importantly, physiologically low concentrations of A{beta}42 demonstrate such ability of monomeric A{beta}42. Extracted cholesterol interacts with A{beta}42 and accelerates its on- membrane aggregation. We propose a model of interaction of A{beta}42 with membranes based on the ability of A{beta}42 to extract cholesterol, which explains several AD associated observations related to cholesterol interplay with A{beta}42 aggregation resulting in the AD onset and progression.
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