Free Cholesterol Accelerates Aβ Self-Assembly on Membranes at Physiological Concentration

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Alzheimer's disease is linked to amyloid-beta (Aβ) aggregation.
• Membrane interactions influence Aβ aggregation, potentially forming neurotoxic species.
• Cholesterol is found in amyloid plaques and may play a role in aggregation.

Purpose of the Study:

• To investigate the impact of membrane composition, specifically cholesterol, on Aβ aggregation.
• To elucidate the mechanisms by which cholesterol affects Aβ aggregation kinetics and aggregate characteristics.
• To explore the role of free cholesterol in Aβ aggregate formation and dissociation.

Main Methods:

• Studied Aβ aggregation in the presence of lipid bilayers with varying cholesterol content.
• Utilized all-atom molecular dynamics simulations to analyze Aβ-cholesterol interactions at a molecular level.
• Quantified aggregation rates, aggregate sizes, and dissociation dynamics.

Main Results:

• Direct Aβ-membrane interactions significantly enhance aggregation, even at low monomer concentrations.
• Cholesterol, both within membranes and as free cholesterol, dramatically accelerates Aβ aggregation kinetics.
• Free cholesterol promotes the rapid formation of larger Aβ aggregates and accelerates their dissociation from lipid bilayers.
• Molecular dynamics simulations revealed cholesterol binding to Aβ monomers, altering conformational ensembles and promoting aggregation.

Conclusions:

• Aβ-lipid interactions, particularly with cholesterol, are critical drivers of amyloid assembly in Alzheimer's disease.
• Cholesterol's presence significantly modulates Aβ aggregation pathways, leading to accelerated formation and release of potentially toxic species.
• Understanding these molecular interactions is vital for developing therapeutic strategies targeting Alzheimer's disease pathogenesis.