Seed-Induced Heterogeneous Cross-Seeding Self-Assembly of Human and Rat Islet Polypeptides

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Amyloid peptides misfold into β-sheet structures, forming aggregates linked to neurodegenerative diseases.
• Amyloid aggregates act as seeds, accelerating further amyloid formation.
• The cross-seeding effects between different amyloid peptides are not well understood.

Purpose of the Study:

• To investigate the cross-seeding possibility and efficiency between human islet amyloid polypeptide (hIAPP) and rat islet amyloid polypeptide (rIAPP).
• To explore how different aggregation phases of hIAPP affect rIAPP aggregation.
• To understand the impact of cross-seeding on cell viability.

Main Methods:

• Utilized various biophysical techniques to study cross-seeding between hIAPP and rIAPP.
• Compared cross-seeding efficiency using preformed hIAPP aggregates at different aggregation phases.
• Assessed cell viability following cross-seeding experiments.

Main Results:

• All tested hIAPP aggregates demonstrated cross-seeding potential for rIAPP, promoting fibril formation with varying efficiencies.
• hIAPP seeds from the growth phase exhibited the strongest cross-seeding potential for rIAPP.
• Homoseeding of hIAPP was more efficient than cross-seeding with rIAPP.
• Cross-seeding at the lag phase reduced cell viability, potentially due to toxic hybrid oligomers.

Conclusions:

• hIAPP aggregates can indeed cross-seed rIAPP, influencing its aggregation pathway.
• The aggregation phase of the seeding peptide significantly impacts cross-seeding efficiency.
• Cross-seeding can generate toxic species, contributing to cellular dysfunction and providing insights into amyloid-related diseases.