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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.

SUBMITTER: Bram Y

PROVIDER: S-EPMC3940978 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Apoptosis induced by islet amyloid polypeptide soluble oligomers is neutralized by diabetes-associated specific antibodies.

Bram Yaron Y Frydman-Marom Anat A Yanai Inbal I Gilead Sharon S Shaltiel-Karyo Ronit R Amdursky Nadav N Gazit Ehud E

Scientific reports 20140304

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 f ...[more]

PMID: 24589570

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Project description:A leading hypothesis for the decimation of insulin-producing β-cells in type 2 diabetes attributes the cause to islet amyloid polypeptide (IAPP) for its deleterious effects on the cell membranes. This idea has produced extensive investigations on human IAPP (hIAPP) and its interactions with lipid bilayers. However, it is still difficult to correlate the peptide-lipid interactions with its effects on islet cells in culture. The hIAPP fibrils have been shown to interact with lipids and damage lipid bilayers, but appear to have no effect on islet cells in culture. Thus, a modified amyloid hypothesis assumes that the toxicity is caused by hIAPP oligomers, which are not preamyloid fibrils or protofibrils. However, so far such oligomers have not been isolated or identified. The hIAPP monomers also bind to lipid bilayers, but the mode of interaction is not clear. Here, we performed two types of experiments that, to our knowledge, have not been done before. We used x-ray diffraction, in conjunction with circular dichroism measurement, to reveal the location of the peptide bound to a lipid bilayer. We also investigated the effects of hIAPP on giant unilamellar vesicles at various peptide concentrations. We obtained the following qualitative results. Monomeric hIAPP binds within the headgroup region and expands the membrane area of a lipid bilayer. At low concentrations, such binding causes no leakage or damage to the lipid bilayer. At high concentrations, the bound peptides transform to β-aggregates. The aggregates exit the headgroup region and bind to the surface of lipid bilayers. The damage by the surface bound β-aggregates depends on the aggregation size. The initial aggregation extracts lipid molecules, which probably causes ion permeation, but no molecular leakage. However, the initial β-aggregates serve as the seed for larger fibrils, in the manner of the Jarrett-Lansbury seeded-polymerization model, that eventually disintegrate lipid bilayers by electrostatic and hydrophobic interactions.

Project description:The accumulation of human islet amyloid polypeptide (hIAPP) on the surface of pancreatic β cells is closely related to the death of the cells. Divalent metal ions play a significant role in the cytotoxicity of hIAPP. In this study, we examined the roles played by the divalent metal ions of zinc, copper and calcium in the aggregation of both hIAPP18-27 fragment and full-length hIAPP and the ability of their oligomers to damage the membrane of POPC/POPG 4 : 1 LUVs using the ThT fluorescence, TEM, AFM, CD, ANS binding fluorescence and dye leakage experiments. We prepared metal-free and metal-associated oligomers that are similar in size and aggregate slowly using the short peptide and confirmed that the ability of the peptide oligomers to damage the lipid membrane is reduced by the binding to the metal ions, which is closely linked to the reducing hydrophobic exposure of the metal-associated oligomers. The study on the full-length hIAPP showed that the observed membrane damage induced by hIAPP oligomers is either mitigated at a peptide-to-metal ratio of 1 : 0.33 or aggravated at a peptide-to-metal ratio of 1 : 1 in the presence of Zn(ii) and Cu(ii), while the surface hydrophobicity of hIAPP oligomers was reduced at both peptide-to-metal ratios. The observed results of the membrane damage were attributed to the counteraction between a decrease in the disruptive ability of metal-associated oligomer species and an increase in the quantity of oligomers promoted by the binding of the metal ions to hIAPP oligomers. The former could play a predominant role in reducing the membrane damage at a peptide-to-metal ratio of 1 : 0.33, while the latter could play a predominant role in enhancing the membrane damage at a peptide-to-metal ratio of 1 : 1. This study shows that an enhanced membrane damage could be caused by the oligomer species with a decreased instead of an increased disruptive ability, given that the abundance of the oligomer species is high enough.

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Apoptosis induced by islet amyloid polypeptide soluble oligomers is neutralized by diabetes-associated specific antibodies.

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Apoptosis induced by islet amyloid polypeptide soluble oligomers is neutralized by diabetes-associated specific antibodies.

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