Conversion between parallel and antiparallel β-sheets in wild-type and Iowa mutant Aβ₄₀ fibrils

Area of Science:

• Biophysics
• Molecular Biology
• Neuroscience

Background:

• Amyloid-beta 40 (Aβ40) fibrils are implicated in neurodegenerative diseases.
• Aβ40 can form fibrils with either parallel or antiparallel β-sheets.
• The Iowa mutation in Aβ40 is associated with increased toxicity.

Purpose of the Study:

• To investigate the conversion pathways between antiparallel and parallel β-sheet fibril structures for wild type and Iowa mutant Aβ40.
• To understand the role of salt bridges in stabilizing different Aβ40 fibril organizations.
• To explore how fibril conversion influences the release of aggregates and potential toxicity, particularly in the Iowa mutant.

Main Methods:

• Utilized a variant of the Hamilton-replica-exchange method for molecular simulations.
• Studied both wild type and Iowa mutant forms of Aβ40.

Main Results:

• Identified distinct salt bridge formations in wild type and Iowa mutant Aβ40.
• These salt bridges stabilize different fibril organizations (antiparallel vs. parallel β-sheets).
• Fibril conversion releases small aggregates, with a notable shift towards toxic oligomers in the Iowa mutant.

Conclusions:

• Salt bridge interactions are critical for determining Aβ40 fibril structure.
• Fibril conversion dynamics differ between wild type and Iowa mutant Aβ40.
• The Iowa mutation's effect on fibril conversion may enhance the formation of toxic oligomers, contributing to disease pathogenesis.