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

Research output: Contribution to journalArticleResearchpeer-review

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, Esteban ; Wang, Bo ; Pilkington, Emily Helen ; Chen, Pengyu ; Kakinen, Aleksandr ; Stanley, William J ; Litwak, Sara Alejandra ; Hanssen, Eric G ; Davis, Thomas Paul ; Ding, Feng ; Ke, Pu Chun. / Inhibition of hIAPP amyloid aggregation and pancreatic β-cell toxicity by OH-terminated PAMAM dendrimer. In: Small. 2016 ; Vol. 12, No. 12. pp. 1615-1626.
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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.",
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month = "3",
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Gurzov, E, Wang, B, Pilkington, EH, Chen, P, Kakinen, A, Stanley, WJ, Litwak, SA, Hanssen, EG, Davis, TP, Ding, F & Ke, PC 2016, 'Inhibition of hIAPP amyloid aggregation and pancreatic β-cell toxicity by OH-terminated PAMAM dendrimer' Small, vol. 12, no. 12, pp. 1615-1626. https://doi.org/10.1002/smll.201502317

Inhibition of hIAPP amyloid aggregation and pancreatic β-cell toxicity by OH-terminated PAMAM dendrimer. / Gurzov, Esteban; Wang, Bo; Pilkington, Emily Helen; Chen, Pengyu; Kakinen, Aleksandr; Stanley, William J; Litwak, Sara Alejandra; Hanssen, Eric G; Davis, Thomas Paul; Ding, Feng; Ke, Pu Chun.

In: Small, Vol. 12, No. 12, 23.03.2016, p. 1615-1626.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Inhibition of hIAPP amyloid aggregation and pancreatic β-cell toxicity by OH-terminated PAMAM dendrimer

AU - Gurzov, Esteban

AU - Wang, Bo

AU - Pilkington, Emily Helen

AU - Chen, Pengyu

AU - Kakinen, Aleksandr

AU - Stanley, William J

AU - Litwak, Sara Alejandra

AU - Hanssen, Eric G

AU - Davis, Thomas Paul

AU - Ding, Feng

AU - Ke, Pu Chun

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