Spectroscopic evidence for polymorphic aggregates formed by amyloid-β fragments

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Amyloid-beta (Aβ) aggregation is central to Alzheimer's disease (AD) pathology.
• Understanding the structural basis of Aβ aggregation is crucial for developing therapeutic strategies.
• Full-length Aβ(1-42) forms mature fibrils, but the behavior of its fragments is less understood.

Purpose of the Study:

• To synthesize and characterize the aggregated structures of three key Aβ(1-42) fragments: Aβ(1-25), Aβ(25-35), and Aβ(33-42).
• To investigate the influence of sequence and pH on the aggregation pathways and resulting conformations of these Aβ fragments.
• To compare the aggregation behavior of Aβ fragments with that of full-length Aβ(1-42).

Main Methods:

• Synthesis of Aβ(1-25), Aβ(25-35), and Aβ(33-42) fragments.
• Linear infrared spectroscopy (amide-I band) to analyze secondary structures (β-sheet, random coil).
• Circular dichroism spectroscopy and transmission electron microscopy to confirm aggregate conformation and morphology.

Main Results:

• Aβ(1-25) and Aβ(33-42) fragments formed mixtures of threadlike β-sheet fibrils, soluble β-sheet oligomers, and random coils, with pH and sequence dependency.
• Aβ(1-25) aggregates showed predominantly antiparallel β-sheets, while Aβ(33-42) exhibited both parallel and antiparallel β-sheet conformations.
• Aβ(25-35) fragment predominantly formed assembled fibrils with parallel β-sheet structures.

Conclusions:

• The aggregation pathway and resulting structures of Aβ fragments are highly dependent on their specific amino acid sequence and environmental pH.
• Unlike full-length Aβ(1-42), these fragments do not exclusively form mature fibrils, suggesting distinct aggregation mechanisms.
• These findings provide critical insights into the structural diversity of Aβ aggregates and their potential roles in Alzheimer's disease pathogenesis.