title: Apoptosis induced by islet amyloid polypeptide soluble oligomers is neutralized by diabetes-associated specific antibodies.
abstract: Soluble oligomeric assemblies of amyloidal proteins appear to act as major pathological agents in several degenerative disorders. Isolation and characterization of these oligomers is a pivotal step towards determination of their pathological relevance. Here we describe the isolation of Type 2 diabetes-associated islet amyloid polypeptide soluble cytotoxic oligomers; these oligomers induced apoptosis in cultured pancreatic cells, permeated model lipid vesicles and interacted with cell membranes following complete internalization. Moreover, antibodies which specifically recognized these assemblies, but not monomers or amyloid fibrils, were exclusively identified in diabetic patients and were shown to neutralize the apoptotic effect induced by these oligomers. Our findings support the notion that human IAPP peptide can form highly toxic oligomers. The presence of antibodies identified in the serum of diabetic patients confirms the pathological relevance of the oligomers. In addition, the newly identified structural epitopes may also provide new mechanistic insights and a molecular target for future therapy.
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Bram
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Frydman-Marom
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Yanai
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Gilead
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Shaltiel-Karyo
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
authors.forename: Nadav
authors.initials: N
authors.lastname: Amdursky
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
authors.forename: Ehud
authors.initials: E
authors.lastname: Gazit
mesh_terms: D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001323:Autoantibodies / Q000276:immunology / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology*; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary
chemical_list: D000906:Antibodies; D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D058228:Islet Amyloid Polypeptide