Bead-Level Characterization of Early-Stage Amyloid β₄₂ Aggregates: Nuclei and Ionic Concentration Effects

Area of Science:

• Biochemistry
• Neuroscience
• Computational Biology

Background:

• Soluble amyloid-beta (Aβ) oligomers, protofibrils, and fibrils are implicated in neurotoxicity.
• Understanding the early stages of Aβ aggregation and the role of salt is crucial for elucidating disease mechanisms.

Purpose of the Study:

• To investigate the aggregation of 75mer Aβ42 oligomers using a coarse-grain model.
• To explore the influence of salt concentration on Aβ aggregation and ion distribution around aggregates.

Main Methods:

• Coarse-grain molecular dynamics simulations.
• Analysis of oligomer morphology, secondary structure content (coil vs. β-turn).
• Investigation of ion shell formation and distribution around Aβ aggregates.

Main Results:

• Oligomer morphology (spherical vs. bar-/disk-shaped) depends on initial conditions (monomers vs. monomers with nuclei).
• Distinct aggregation mechanisms (master-nucleus vs. multi-nuclei) were observed.
• A unique two-fold ion gap formed at 100 mM NaCl, suggesting physiological relevance.
• An ion-solute cutoff distance of 0.66 nm was predicted.

Conclusions:

• Initial aggregation conditions significantly alter Aβ oligomer structure and aggregation pathways.
• Salt ions form distinct shells around aggregates, with physiological salt concentrations showing unique patterns.
• The findings provide a generalized model for ion distribution in biomolecular aggregation systems.