Does amyloid fibril nucleation occur at surfaces only?

Area of Science:

• Biophysical Chemistry
• Neurodegenerative Diseases
• Protein Folding Dynamics

Background:

• Alzheimer disease is linked to the aggregation of amyloid-beta 42 (Aβ42) peptides into amyloid fibrils.
• In vitro experiments are crucial for understanding the biophysical chemistry of amyloid formation.
• Previous studies have explored Aβ42 fibril formation, but the nucleation mechanism requires further elucidation.

Purpose of the Study:

• To investigate the primary nucleation mechanism of Aβ42 fibril formation in vitro.
• To determine whether homogeneous or heterogeneous nucleation is the dominant pathway.
• To explore the role of interfaces and protein folding in Aβ42 nucleation.

Main Methods:

• In vitro experiments were conducted to study the homogeneous nucleation of Aβ42 fibrils.
• Analysis focused on the kinetics and conditions favoring primary nucleation.
• Theoretical considerations regarding protein folding and Levinthal's paradox were applied.

Main Results:

• Homogeneous primary nucleation of Aβ42 fibrils in solution is a rare event.
• Nucleation predominantly occurs via heterogeneous nucleation at interfaces.
• Heterogeneous nucleation is significantly faster and is proposed to be catalyzed by surface adsorption.

Conclusions:

• Amyloid fibril formation of Aβ42 peptides is primarily driven by heterogeneous nucleation at surfaces.
• Surface adsorption reduces the conformational search space for monomers, facilitating the target fold.
• Understanding nucleation mechanisms is key to developing therapeutic strategies for Alzheimer disease.