Active Immunization Against hIAPP Oligomers Ameliorates the Diabetes- Associated Phenotype in a Transgenic Mice Model

Abstract Type 2 diabetes is characterized by insulin tolerance in target cells followed by a reduction of pancreatic β-cell mass. Islet amyloid polypeptide oligomeric assemblies were shown to contribute to β-cell apoptosis by forming discrete pores that destabilize the cellular membrane. We previous...

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Autores principales:	Yaron Bram, Sivan Peled, Sayanti Brahmachari, Michael Harlev, Ehud Gazit
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d9a8a5b39d4c45a2aef9fe124103493e
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spelling	oai:doaj.org-article:d9a8a5b39d4c45a2aef9fe124103493e2021-12-02T11:52:17ZActive Immunization Against hIAPP Oligomers Ameliorates the Diabetes- Associated Phenotype in a Transgenic Mice Model10.1038/s41598-017-14311-12045-2322https://doaj.org/article/d9a8a5b39d4c45a2aef9fe124103493e2017-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-14311-1https://doaj.org/toc/2045-2322Abstract Type 2 diabetes is characterized by insulin tolerance in target cells followed by a reduction of pancreatic β-cell mass. Islet amyloid polypeptide oligomeric assemblies were shown to contribute to β-cell apoptosis by forming discrete pores that destabilize the cellular membrane. We previously characterized α-helical cytotoxic islet amyloid polypeptide oligomers which interact with cell membranes, following a complete internalization that leads to cellular apoptosis. Moreover, antibodies which bind the oligomers and neutralize the cytotoxicity were exclusively identified in the serum of type 2 diabetes patients. Here, we examined the usage of the newly characterized oligomers as an active immunization agent targeting amyloid self- assembly in a diabetes-associated phenotype transgenic mice model. Immunized transgenic mice showed an increase in hIAPP-antibody serum titer as well as improvement in diabetes-associated parameters. Lower fasting blood glucose levels, higher insulin, and lower islet amyloid polypeptide accumulation were observed. Furthermore, antibodies derived from the immunized mice reduced hIAPP oligomers cytotoxicity towards β-cells in a dose-dependent manner. This study highlights the significance of targeting the early amyloid self-assembly events for potential disease management. Furthermore, it demonstrates that α-helical oligomers conformers are valid epitope for the development of future immunization therapy.Yaron BramSivan PeledSayanti BrahmachariMichael HarlevEhud GazitNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yaron Bram Sivan Peled Sayanti Brahmachari Michael Harlev Ehud Gazit Active Immunization Against hIAPP Oligomers Ameliorates the Diabetes- Associated Phenotype in a Transgenic Mice Model
description	Abstract Type 2 diabetes is characterized by insulin tolerance in target cells followed by a reduction of pancreatic β-cell mass. Islet amyloid polypeptide oligomeric assemblies were shown to contribute to β-cell apoptosis by forming discrete pores that destabilize the cellular membrane. We previously characterized α-helical cytotoxic islet amyloid polypeptide oligomers which interact with cell membranes, following a complete internalization that leads to cellular apoptosis. Moreover, antibodies which bind the oligomers and neutralize the cytotoxicity were exclusively identified in the serum of type 2 diabetes patients. Here, we examined the usage of the newly characterized oligomers as an active immunization agent targeting amyloid self- assembly in a diabetes-associated phenotype transgenic mice model. Immunized transgenic mice showed an increase in hIAPP-antibody serum titer as well as improvement in diabetes-associated parameters. Lower fasting blood glucose levels, higher insulin, and lower islet amyloid polypeptide accumulation were observed. Furthermore, antibodies derived from the immunized mice reduced hIAPP oligomers cytotoxicity towards β-cells in a dose-dependent manner. This study highlights the significance of targeting the early amyloid self-assembly events for potential disease management. Furthermore, it demonstrates that α-helical oligomers conformers are valid epitope for the development of future immunization therapy.
format	article
author	Yaron Bram Sivan Peled Sayanti Brahmachari Michael Harlev Ehud Gazit
author_facet	Yaron Bram Sivan Peled Sayanti Brahmachari Michael Harlev Ehud Gazit
author_sort	Yaron Bram
title	Active Immunization Against hIAPP Oligomers Ameliorates the Diabetes- Associated Phenotype in a Transgenic Mice Model
title_short	Active Immunization Against hIAPP Oligomers Ameliorates the Diabetes- Associated Phenotype in a Transgenic Mice Model
title_full	Active Immunization Against hIAPP Oligomers Ameliorates the Diabetes- Associated Phenotype in a Transgenic Mice Model
title_fullStr	Active Immunization Against hIAPP Oligomers Ameliorates the Diabetes- Associated Phenotype in a Transgenic Mice Model
title_full_unstemmed	Active Immunization Against hIAPP Oligomers Ameliorates the Diabetes- Associated Phenotype in a Transgenic Mice Model
title_sort	active immunization against hiapp oligomers ameliorates the diabetes- associated phenotype in a transgenic mice model
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d9a8a5b39d4c45a2aef9fe124103493e
work_keys_str_mv	AT yaronbram activeimmunizationagainsthiappoligomersamelioratesthediabetesassociatedphenotypeinatransgenicmicemodel AT sivanpeled activeimmunizationagainsthiappoligomersamelioratesthediabetesassociatedphenotypeinatransgenicmicemodel AT sayantibrahmachari activeimmunizationagainsthiappoligomersamelioratesthediabetesassociatedphenotypeinatransgenicmicemodel AT michaelharlev activeimmunizationagainsthiappoligomersamelioratesthediabetesassociatedphenotypeinatransgenicmicemodel AT ehudgazit activeimmunizationagainsthiappoligomersamelioratesthediabetesassociatedphenotypeinatransgenicmicemodel
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Active Immunization Against hIAPP Oligomers Ameliorates the Diabetes- Associated Phenotype in a Transgenic Mice Model

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