Static and dynamic disorder in Aβ40 fibrils

Area of Science:

• Biophysics
• Neuroscience
• Structural Biology

Background:

• Amyloid-beta (Aβ) fibril deposition is a key feature of Alzheimer's disease.
• Understanding Aβ fibril structure and dynamics is crucial for developing Alzheimer's therapies.

Purpose of the Study:

• To investigate the structure and dynamics of Aβ40 fibrils using site-directed spin labeling and EPR spectroscopy.
• To compare the structural characteristics of Aβ40 and Aβ42 fibrils.

Main Methods:

• Site-directed spin labeling of Aβ40 peptides.
• Electron Paramagnetic Resonance (EPR) spectroscopy.
• Spectral simulations to analyze spin exchange and mobility.

Main Results:

• Aβ40 fibrils, except for residue D1, are highly ordered.
• Hydrophobic regions (residues 17-20 and 31-36) exhibit minimal static disorder.
• Aβ40 fibrils show more ordered packing than Aβ42 fibrils, with an ordered C-terminus.
• Residues 22 and 23 display the highest dynamic disorder.

Conclusions:

• Static disorder, not dynamic disorder, primarily influences spin exchange in Aβ40 fibrils.
• Structural differences, particularly in the C-terminus, may explain why Aβ42 fibrils are more prone to aggregation and defects.
• Findings offer insights into Alzheimer's pathogenesis and potential therapeutic interventions targeting fibril structure.