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The toxic nature of murine amylin and the immune responsivity of pancreatic islet to conformational antibody in mice

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Abstract

The human amylin is a pancreatic peptide hormone found in hyperhormonemic state along with insulin in subclinical diabetes. Amylin has been associated with the pathology of type 2 diabetes, particularly due to its ability to assembly into toxic oligomers and amyloid specimens. On the other hand, some variants such as murine amylin has been described as non-amyloidogenic, either in vitro or in vivo. Recent data have demonstrated the amyloid propensity of murine amylin and the therapeutic analogue pramlintide, suggesting a universality for amylin amyloidosis. Here, we report the amyloidogenesis of murine amylin, which showed lower responsivity to the fluorescent probe thioflavin T compared to human amylin, but presented highly organized fibrilar amyloid material. The aggregation of murine amylin also resulted in the formation of cytotoxic specimens, as evaluated in vitro in INS-1 cells. The aggregation product from murine amylin was responsive to a specific antibody raised against amyloid oligomers, the A11 oligomer antibody. Pancreatic islets of wild-type Swiss male mice have also shown responsivity for the anti-oligomer, indicating the natural abundance of such specimen in rodents. These data provide for the first time evidences for the toxic nature of oligomeric assemblies of murine amylin and its existence in wild-type, non-transgenic mice.

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Abbreviations

IAPP:

Islet amyloid polypeptide

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Acknowledgements

We would like to thank Dr. Ivone Rosa for excellent technical services, to Dr. Guilherme Augusto (IBqM) for helpful assistance in setting-up dot-blot assays, and to DIMAV-INMETRO and CENABIO-UFRJ for providing access to their analytical platforms. This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro Carlos Chagas Filho (FAPERJ). The funding agencies had no role in the study design, data collection and analysis, or decision to publish or prepare of the manuscript.

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Authors and Affiliations

  1. Federal University of Rio de Janeiro – UFRJ, CCS, Bss24, Ilha do Fundão, Rio de Janeiro, RJ, 21941-590, Brazil

    Luiza C. S. Erthal, Luana Jotha-Mattos, Cinthia Melo Costa, Kleber L. A. Souza & Luís Maurício T. R. Lima

  2. Oswaldo Cruz Foundation, Rio de Janeiro, RJ, 21040-360, Brazil

    Flávio Alves Lara, Sabrina Alves dos Reis & Bernardo Miguel de Oliveira Pascarelli

  3. Laboratory for Macromolecules (LAMAC-DIMAV), Brazilian National Institute of Metrology, Quality and Technology - INMETRO, Av. N. Sa. das Graças, 50 - Xerém, Duque de Caxias, Rio de Janeiro, RJ, 25250-020, Brazil

    Luís Maurício T. R. Lima

  4. National Institute of Science and Technology for Structural Biology and Bioimaging (INBEB-INCT), Federal University of Rio de Janeiro, Rio de Janeiro, 21941-590, Brazil

    Luís Maurício T. R. Lima

  5. School of Pharmacy, Federal University of Rio de Janeiro – UFRJ, Av. Carlos Chagas Filho, 373, CCS, Bss24, Ilha do Fundão, Rio de Janeiro, RJ, 21941-590, Brazil

    Luís Maurício T. R. Lima

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  1. Luiza C. S. Erthal
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Correspondence to Luís Maurício T. R. Lima.

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The authors have no financial conflicts of interest with the contents of this article. LMTRL is a participant in patent applications by the UFRJ on controlled release of peptides.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Erthal, L.C.S., Jotha-Mattos, L., Lara, F.A. et al. The toxic nature of murine amylin and the immune responsivity of pancreatic islet to conformational antibody in mice. Mol Cell Biochem 447, 1–7 (2018). https://doi.org/10.1007/s11010-018-3288-x

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  • DOI: https://doi.org/10.1007/s11010-018-3288-x

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