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There is a role for proIAPP in islet amyloid fibrillogenesis
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Amyloid Unit, Institute for Molecular and Cell Biology, Porto, Portugal.
Physiological-Chemical Institute, University of Tübingen, Tübingen, Germany.
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2008 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Islet amyloid polypeptide (IAPP) can aggregate into amyloid, a common pathological finding present extracellularly in the islets of Langerhans in individuals with type 2 diabetes. IAPP arises from posttranslational processing of the precursor proIAPP. Accumulation of proIAPP in the secretory granules can result in proIAPP-amyloid formation. We raise the following hypothesis; proIAPP can under not yet defined circumstances aggregate into amyloid-like fibrils intracellularly and at this location act as template and cross-seed amyloid formation of IAPP. We have produced recombinant peptides corresponding to proIAPP and IAPP. These peptides aggregate readily into fibrils with typical amyloid characteristics. Sonicated recproIAPP- and recIAPP- preformed fibrillar aggregates were injected intravenously to +/hIAPP/-mIAPP transgenic mice. Male mice from this strain develop islet amyloid in response to high fat diet. Control animals received an injection of preformed amyloid fibrils from the proinsulin processing intermediate (C-peptide/A-chain) or sodium chloride. All animals were fed a diet high in fat over a ten month period. The presence of islet amyloid was studied after Congo red staining. We found amyloid in 20 % of the islets in animals injected with preformed recIAPP fibrils and in 10 % of the islets in animals injected with preformed recproIAPP fibrils. Control animals developed amyloid in 1-2% of the islets. Our results support the hypothesis that proIAPP-fibrils can act as template and induce conformational changes in soluble IAPP that results in propagation of the amyloid fibrils. This is the first report on in vivo seeding of a localized amyloid form and we present data that support transport of amyloid between islets as a putative route for the spreading of islet amyloid. Our finding suggests that therapies, which use capping of fibril endings, might be useless.

Place, publisher, year, edition, pages
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-73476OAI: diva2:472836
Available from: 2012-01-04 Created: 2012-01-04 Last updated: 2012-01-04Bibliographically approved
In thesis
1. Proislet Amyloid Polypeptide (proIAPP): Impaired Processing is an Important Factor in Early Amyloidogenesis in Type 2 Diabetes
Open this publication in new window or tab >>Proislet Amyloid Polypeptide (proIAPP): Impaired Processing is an Important Factor in Early Amyloidogenesis in Type 2 Diabetes
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyloid is defined as extracellular protein aggregates with a characteristic fibrillar ultra-structure, Congo red affinity and a unique x-ray diffraction pattern. At present, 25 different human amyloid fibril proteins have been identified, and amyloid aggregation is associated with pathological manifestations such as Alzheimer’s disease, spongiform encephalopathy and type 2 diabetes. Amyloid aggregation triggers apoptosis by incorporation of early oligomers in cellular membranes, causing influx of ions. Amyloid is the only visible pathological islet alteration in subjects with type 2 diabetes, and islet amyloid polypeptide (IAPP) is the major islet amyloid fibril component. IAPP is produced by beta-cells and co-localized with insulin in the secretory granules. Both peptides are synthesised as pro-molecules and undergo proteolytic cleavage by the prohormone convertase 1/3 and 2. Although IAPP is the main amyloid constituent, both proIAPP and proIAPP processing intermediates have been identified in islet amyloid.

The aim of this thesis was to study the role of impaired processing of human proIAPP in early islet amyloidogenesis. Five cell lines with individual processing properties were transfected with human proIAPP and expression, aggregation and viability were studied. Cells unable to process proIAPP into IAPP or to process proIAPP at the N-terminal processing site accumulated intracellular amyloid-like aggregates and underwent apoptosis. Further, proIAPP immunoreactivity was detected in intracellular amyloid-like aggregates in betacells from transgenic mice expressing human IAPP and in transplanted human beta-cells. ProIAPP was hypothesized to act as a nidus for further islet amyloid deposition, and to investigate this theory, amyloid-like fibrils produced from recombinant IAPP, proIAPP and insulin C-peptide/A-chain were injected in the tail vein of transgenic mice expressing the gene for human IAPP. Pancreata were recovered after 10 months and analysed for the presence of amyloid. Both IAPP and proIAPP fibrils but not des-31,32 proinsulin fibrils, caused an increase in affected islets and also an increase of the amyloid amount. This finding demonstrates a seeding capacity of proIAPP on IAPP fibrillogenesis. IAPP has been known for some time to trigger apoptosis in cultured cells, and a novel method for real time detection of apoptosis in beta-cells was developed. Aggregation of recombinant proIAPP and proIAPP processing intermediates were concluded to be inducers of apoptosis as potent as IAPP fibril formation.

From the results of this study, a scenario for initial islet amyloidogenesis is proposed. Initial amyloid formation occurs intracellularly as a result of alterations in beta-cell processing capacity. When the host cell undergoes apoptosis intracellular proIAPP amyloid becomes extracellular and can act as seed for further islet amyloid deposition.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2006. 74 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 967
Biosynthesis amyloid, Genetics amyloid, Metabolism amyloid, Islets of Langerhans, Proprotein convertases, Posttranslation protein processing
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
urn:nbn:se:liu:diva-8243 (URN)91-85643-59-9 (ISBN)
Public defence
2006-11-24, Berzeliussalen, Campus US, Linköpings Universitet, Linköping, 13:15 (English)
Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2012-01-04Bibliographically approved

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