Inhibition of hIAPP amyloid aggregation and pancreatic β-cell toxicity by OH-terminated PAMAM dendrimer

Esteban Gurzov, Bo Wang, Emily Helen Pilkington, Pengyu Chen, Aleksandr Kakinen, William J Stanley, Sara Alejandra Litwak, Eric G Hanssen, Thomas Paul Davis, Feng Ding, Pu Chun Ke

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Abstract

Human islet amyloid polypeptide (hIAPP, or amylin) forms amyloid deposits in the islets of Langerhans, a phenomenon that is associated with type-2 diabetes impacting millions of people worldwide. Accordingly, strategies against hIAPP aggregation are essential for the prevention and eventual treatment of the disease. Here, it is shown that generation-3 OH-terminated poly(amidoamine) dendrimer, a polymeric nanoparticle, can effectively halt the aggregation of hIAPP and shut down hIAPP toxicity in pancreatic MIN6 and NIT-1 cells as well as in mouse islets. This finding is supported by high-throughput dynamic light scattering experiment and thioflavin T assay, where the rapid evolution of hIAPP nucleation and elongation processes is halted by the addition of the dendrimer up to 8 h. Discrete molecular dynamics simulations further reveal that hIAPP residues bound strongly with the dendrimer near the c-terminal portion of the peptide, where the amyloidogenic sequence (residues 22-29) locates. Furthermore, simulations of hIAPP dimerization reveal that binding with the dendrimer significantly reduces formation of interpeptide contacts and hydrogen bonds, thereby prohibiting peptide self-association and amyloidosis. This study points to a promising nanomedicinal strategy for combating type-2 diabetes and may have broader implications for targeting neurological disorders whose distinct hallmark is also amyloid fibrillation.
Original languageEnglish
Pages (from-to)1615-1626
Number of pages12
JournalSmall
Volume12
Issue number12
DOIs
Publication statusPublished - 23 Mar 2016

Keywords

  • Amyloid fibrillation
  • Cytotoxicity
  • Discrete molecular dynamics simulations
  • High-throughput dynamic light scattering
  • Human islet amyloid polypeptide
  • Hydroxyl-terminated polyamidoamine dendrimer
  • Protein aggregation

Cite this

Gurzov, E., Wang, B., Pilkington, E. H., Chen, P., Kakinen, A., Stanley, W. J., Litwak, S. A., Hanssen, E. G., Davis, T. P., Ding, F., & Ke, P. C. (2016). Inhibition of hIAPP amyloid aggregation and pancreatic β-cell toxicity by OH-terminated PAMAM dendrimer. Small, 12(12), 1615-1626. https://doi.org/10.1002/smll.201502317