Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics
- New York University School of Medicine, United States
- Novo Nordisk, Denmark
- Stony Brook University, United States
- PhaseTech Spectroscopy, Inc., United States
- University of Wisconsin-Madison, United States
- University of British Columbia, Canada
Abstract
Islet amyloidosis by IAPP contributes to pancreatic β-cell death in diabetes, but the nature of toxic IAPP species remains elusive. Using concurrent time-resolved biophysical and biological measurements, we define the toxic species produced during IAPP amyloid formation and link their properties to induction of rat INS-1 β-cell and murine islet toxicity. These globally flexible, low order oligomers upregulate pro-inflammatory markers and induce reactive oxygen species. They do not bind 1-anilnonaphthalene-8-sulphonic acid and lack extensive β-sheet structure. Aromatic interactions modulate, but are not required for toxicity. Not all IAPP oligomers are toxic; toxicity depends on their partially structured conformational states. Some anti-amyloid agents paradoxically prolong cytotoxicity by prolonging the lifetime of the toxic species. The data highlight the distinguishing properties of toxic IAPP oligomers and the common features that they share with toxic species reported for other amyloidogenic polypeptides, providing information for rational drug design to treat IAPP induced β-cell death.
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Animal experimentation: All procedures were approved by the Institutional Animal Care and Use Committee of New York University Langone Medical Center (NYULMC) and conform to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH) (8th Edition, 2011, ISBN 10: 0-309-15400-6). The Animal Care and Use Program at NYULMC are in full compliance with NIH policy (NYULMC Compliance Number is A3435-01).
Copyright
© 2016, Abedini et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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