Evaluation of membrane models and their composition for islet amyloid polypeptide-membrane aggregation

Area of Science:

• Biochemistry
• Cell Biology
• Materials Science

Background:

• Human islet amyloid polypeptide (IAPP) aggregation into amyloid fibrils is implicated in pancreatic islet β-cell death in type 2 diabetes mellitus (T2DM).
• IAPP interacts with lipid membranes, but the influence of varying membrane compositions and models on fibril formation remains unclear.

Purpose of the Study:

• To systematically analyze how different lipid compositions and membrane mimetics affect IAPP fibril formation kinetics and morphology.
• To understand the role of membrane properties in IAPP-mediated β-cell pathogenesis.

Main Methods:

• Investigated IAPP interaction with various membrane models, including micelles (SDS, DPC), bicelles (DMPC/DHPC), small unilamellar vesicles (SUVs), and large unilamellar vesicles (LUVs).
• Analyzed the effect of lipid composition (e.g., charged lipids, phosphatidylethanolamine, cholesterol) on IAPP aggregation.
• Monitored fibril formation kinetics and morphology using biophysical techniques.

Main Results:

• Micelles (SDS, DPC) stabilized α-helical IAPP, potentially preserving monomeric or small oligomeric species.
• Zwitterionic bicelles and SUVs accelerated IAPP fibril formation compared to LUVs, highlighting the impact of membrane size and curvature.
• Negatively charged membranes reduced lag-time, while phosphatidylethanolamine and cholesterol modulated aggregation, likely by altering membrane properties or direct IAPP interaction.
• Lipid composition influenced both fibril growth on membrane surfaces and interactions of β-sheet oligomers with membranes.

Conclusions:

• Membrane mimetics and lipid composition significantly modulate IAPP fibril formation pathways and kinetics.
• Membrane properties play a crucial role in IAPP aggregation and its potential contribution to T2DM pathogenesis.
• Understanding these interactions is vital for developing therapeutic strategies targeting IAPP-related β-cell dysfunction.