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Published on: September 28, 2019
Fiber-dependent and -independent toxicity of islet amyloid polypeptide
Diana E Schlamadinger1, Andrew D Miranker1
1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut.
Abstract:
The 37-residue peptide hormone islet amyloid polypeptide (IAPP) plays a central role in diabetes pathology. Although its amyloid fiber aggregation kinetics and cytotoxicity to β-cells are well documented, few reports have directly assessed the role of fibers in cell-based toxicity experiments. Here, we report that amyloid formation of IAPP can be strongly inhibited by the extracellular environment of live cells. For example, fiber formation is more strongly suppressed in cell culture medium than in aqueous buffer. The serum component of the medium is responsible for this inhibition. Although amyloid formation was previously shown to be catalyzed by both synthetic and chloroform-extracted phospholipid surfaces, it is instead inhibited by membrane surfaces prepared directly from the plasma membranes of an immortal β-cell line. This disparity is reconciled by direct assessment of fibers in cell-culture-based toxicity experiments. We discovered that fibers are nontoxic if they are washed free of adsorbed nonfibrillar components. Moreover, toxicity is not only rescued when monomers are added back to fibers but is greater than what is observed from the precursor alone. Our results are interpreted in light of the capacity of the fiber surface to template amyloid nucleation.
Insights
Islet amyloid polypeptide (IAPP) fiber formation, linked to diabetes, is surprisingly inhibited by cell environments. Washed IAPP fibers are non-toxic, with toxicity increasing when monomers re-adsorb.
Area of Science:
- Biochemistry
- Cell Biology
- Diabetes Research
Background:
- Islet amyloid polypeptide (IAPP) aggregation into amyloid fibers is implicated in diabetes pathology.
- Previous studies documented IAPP fiber kinetics and β-cell cytotoxicity, but direct assessment in cell-based toxicity experiments was limited.
Purpose of the Study:
- To investigate the role of IAPP fibers in cell-based toxicity experiments.
- To elucidate the influence of the extracellular environment on IAPP amyloid formation and toxicity.
Main Methods:
- Assessing IAPP amyloid formation in cell culture medium versus aqueous buffer.
- Investigating the inhibitory effect of serum and cell membrane surfaces on IAPP aggregation.
- Evaluating the cytotoxicity of washed IAPP fibers and re-adsorbed monomers using cell-based assays.
Main Results:
- IAPP amyloid formation is significantly inhibited by the extracellular environment of live cells, particularly by serum components in cell culture medium.
- Unlike synthetic surfaces, plasma membrane surfaces from β-cells inhibit IAPP fiber formation.
- Washed IAPP amyloid fibers are non-toxic; toxicity is observed when non-fibrillar components re-adsorb or when monomers are added back, exceeding precursor toxicity.
Conclusions:
- The extracellular environment modulates IAPP amyloid formation, with cell membranes acting as inhibitors.
- The apparent toxicity of IAPP fibers depends on adsorbed non-fibrillar components.
- IAPP fiber surfaces can template amyloid nucleation, influencing toxicity in a manner dependent on monomer interaction.
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