Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics

Andisheh Abedini, Annette Plesner, Ping Cao, Zachary Ridgway, Jinghua Zhang, Ling Hsien Tu, Chris T. Middleton, Brian Chao, Daniel J. Sartori, Fanling Meng, Hui Wang, Amy G. Wong, Martin T. Zanni, C. Bruce Verchere, Daniel P. Raleigh, Ann Marie Schmidt

Research output: Contribution to journalArticle

41 Citations (Scopus)

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.

Original languageEnglish
JournaleLife
Volume5
DOIs
Publication statusPublished - 2016 May 23

Fingerprint

Time and motion study
Poisons
Amyloidosis
Oligomers
Toxicity
Cell death
Amyloid
Cell Death
Therapeutics
Sulfonic Acids
Drug Design
Cytotoxicity
Medical problems
Islets of Langerhans
Rats
Reactive Oxygen Species
Up-Regulation
Peptides
Pharmaceutical Preparations

Keywords

  • IAPP
  • amylin
  • amyloid
  • biochemistry
  • biophysics
  • diabetes
  • islet amyloid polypeptide
  • mouse
  • oligomer
  • rat
  • structural biology

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics. / Abedini, Andisheh; Plesner, Annette; Cao, Ping; Ridgway, Zachary; Zhang, Jinghua; Tu, Ling Hsien; Middleton, Chris T.; Chao, Brian; Sartori, Daniel J.; Meng, Fanling; Wang, Hui; Wong, Amy G.; Zanni, Martin T.; Verchere, C. Bruce; Raleigh, Daniel P.; Schmidt, Ann Marie.

In: eLife, Vol. 5, 23.05.2016.

Research output: Contribution to journalArticle

Abedini, A, Plesner, A, Cao, P, Ridgway, Z, Zhang, J, Tu, LH, Middleton, CT, Chao, B, Sartori, DJ, Meng, F, Wang, H, Wong, AG, Zanni, MT, Verchere, CB, Raleigh, DP & Schmidt, AM 2016, 'Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics', eLife, vol. 5. https://doi.org/10.7554/eLife.12977
Abedini, Andisheh ; Plesner, Annette ; Cao, Ping ; Ridgway, Zachary ; Zhang, Jinghua ; Tu, Ling Hsien ; Middleton, Chris T. ; Chao, Brian ; Sartori, Daniel J. ; Meng, Fanling ; Wang, Hui ; Wong, Amy G. ; Zanni, Martin T. ; Verchere, C. Bruce ; Raleigh, Daniel P. ; Schmidt, Ann Marie. / Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics. In: eLife. 2016 ; Vol. 5.
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