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

作者：Bram Yaron; Peled Sivan; Brahmachari Sayanti; Harlev Michael; Gazit Ehud^*

来源：Scientific Reports, 2017, 7(1): 14031.

DOI：10.1038/s41598-017-14311-1

Type 2 diabetes is characterized by insulin tolerance in target cells followed by a reduction of pancreatic beta-cell mass. Islet amyloid polypeptide oligomeric assemblies were shown to contribute to beta-cell apoptosis by forming discrete pores that destabilize the cellular membrane. We previously characterized a-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 beta-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 a-helical oligomers conformers are valid epitope for the development of future immunization therapy.

• 出版日期2017-10-25