Sterol-activated amyloid beta fibril formation.

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Alzheimer's disease (AD) is linked to brain cholesterol, but mechanisms are unclear.
• Amyloid beta (Aβ) plaque accumulation precedes AD symptoms.
• Cholesterol and metabolites are known to accelerate Aβ plaque formation.

Purpose of the Study:

• To investigate the mechanism by which cholesterol (CH) and cholesterol 3-sulfate (CS) accelerate Aβ42 fibril formation.
• To quantify the effects of CH and CS on Aβ42 polymerization kinetics and structure.

Main Methods:

• Quantitative ligand binding assays
• Aβ42 fibril polymerization studies
• Molecular dynamics simulations

Main Results:

• CH and CS bind Aβ42 in a 1:1 stoichiometry, accelerating nucleation.
• CS accelerated nucleation ~13,000-fold, while CH accelerated it ~49-fold.
• Molecular dynamics revealed ligand-induced stabilization of non-helical Aβ42 conformations.

Conclusions:

• Cholesterol and its metabolite CS significantly accelerate Aβ42 fibril formation via a nucleation-dependent mechanism.
• Ligand binding stabilizes rate-limiting non-helical conformations, promoting rapid polymerization.
• Findings suggest cholesterol metabolism is a key factor in AD pathogenesis and a potential therapeutic target.