Sticker-and-spacer model for amyloid beta condensation and fibrillation

Area of Science:

• Biophysics
• Neurodegenerative Diseases
• Computational Biology

Background:

• Alzheimer's disease (AD) is characterized by neurotoxic amyloid beta (Aβ) plaques.
• Aβ₁₋₄₂ is disproportionately found in plaques despite Aβ₁₋₄₀ being more abundant.
• The mechanism driving this Aβ₁₋₄₂ enrichment remains unclear.

Purpose of the Study:

• To investigate the hypothesis that differential hydrophobicity drives Aβ₁₋₄₂ enrichment in plaques.
• To explore the role of liquid-liquid phase-separation (LLPS) in Aβ aggregation and plaque formation.

Main Methods:

• Development of a molecular 'sticker-and-spacer lattice model' for unfolded Aβ.
• Simulation of reversible dimerization and chain elongation of Aβ peptides.
• Analysis of excluded-volume interactions, hydrophobic interactions, and LLPS phenomena.

Main Results:

• The model demonstrates that hydrophobic interactions in Aβ chains promote cooperative growth.
• Sufficient hydrophobicity drives LLPS, forming condensates that nucleate fiber formation.
• A small fraction of Aβ₁₋₄₀ in mixtures lowers the critical concentration for LLPS.

Conclusions:

• Theoretical support for LLPS condensates as precursors to Aβ aggregation.
• Hydrophobic interactions provide a mechanistic explanation for Aβ₁₋₄₂ enrichment in Alzheimer's disease aggregates.
• The findings offer insights into the early stages of amyloid plaque formation in AD.