Synthetic toxic Aβ_1-42 oligomers can assemble in different morphologies

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Alzheimer's disease (AD) is a leading neurodegenerative disorder characterized by amyloid-beta (Aβ) peptide aggregation.
• Aβ oligomers, particularly intermediate forms, are implicated in disrupting cell membrane integrity, a key factor in AD pathogenesis.
• A synthetic Aβ1-42 mutant, G37C, was engineered for enhanced toxicity and stable oligomer formation.

Purpose of the Study:

• To investigate the structural and biophysical properties of toxic Aβ oligomers.
• To elucidate the mechanism by which Aβ oligomers disrupt membrane integrity.
• To characterize the assembly pathway of the AβG37C mutant.

Main Methods:

• Fluorescence spectroscopy
• Cross-linking assays
• Mass spectrometry (MS)
• Small-angle X-ray scattering (SAXS)
• Atomic force microscopy (AFM)
• Transmission electron microscopy (TEM)
• Calcein leakage assays

Main Results:

• The AβG37C mutant forms stable oligomers, primarily 14-mers, derived from disulfide-linked homodimers.
• These disulfide-stabilized oligomers exhibit significant membrane-disrupting activity.
• Oligomer formation via disulfide bonds inhibits the assembly into typical amyloid fibrils.
• Reduction of disulfide bonds triggers rearrangement and promotes amyloid fibril formation.

Conclusions:

• The toxic AβG37C mutant forms unusual amyloid structures with anti-parallel β-sheets via disulfide-linked oligomers.
• These oligomers are directly responsible for membrane damage, a critical event in Alzheimer's disease.
• The ability to generate stable, detergent-free oligomers facilitates further studies on their assembly and membrane interactions.