Amyloid β 42 fibril structure based on small-angle scattering.

Area of Science:

• Biophysics
• Neuroscience
• Structural Biology

Background:

• Amyloid fibrils, particularly amyloid-beta 42 (Aβ42), are implicated in Alzheimer's disease pathogenesis.
• Aβ42 fibril surface toxicity arises from the generation of toxic oligomers, highlighting the need for structural insights.
• Understanding fibril structure is critical for developing targeted therapeutic strategies.

Purpose of the Study:

• To determine the cross-section dimension and shape of Aβ42 fibrils.
• To develop a detailed atomistic model of Aβ42 fibril structure.
• To investigate the stability and arrangement of filaments within Aβ42 fibrils.

Main Methods:

• Small-angle scattering (SAS) was employed to analyze Aβ42 fibrils prepared under specific conditions.
• Continuum and atomistic modeling, including Rosetta optimization and fitting to SAS data, were used to elucidate fibril structure.
• Solid-state NMR data (PDB ID 5kk3) served as a starting point for atomistic model development.

Main Results:

• SAS data revealed an elliptical cross-section for Aβ42 fibrils with a mass-per-unit length consistent with two filaments, each containing two monomers arranged in planes.
• Atomistic modeling resulted in a two-filament model with twofold rotation symmetry around the fibril axis, incorporating residues 11-42.
• No observed polydispersity in filament number across samples suggests a stable, energetically favorable two-filament arrangement.

Conclusions:

• The study provides a high-resolution atomistic model of Aβ42 fibrils, revealing a stable two-filament structure.
• This structural characterization offers valuable insights into the mechanism of Aβ42 fibril toxicity.
• The findings support the two-filament arrangement as a potential therapeutic target for Alzheimer's disease.