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In Vivo Seeding and Cross-Seeding of Localized Amyloidosis A Molecular Link between Type 2 Diabetes and Alzheimer Disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
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2015 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 185, no 3, 834-846 p.Article in journal (Refereed) Published
Abstract [en]

Several proteins have been identified as amyloid forming in humans, and independent of protein origin, the fibrils are morphologically similar. Therefore, there is a potential for structures with amyloid seeding ability to induce both homologous and heterologous fibril growth; thus, molecular interaction can constitute a Link between different amyloid forms. Intravenous injection with preformed fibrils from islet amyloid polypeptide (IAPP), proIAPP, or amyloid-beta (A beta) into human IAPP transgenic mice triggered IAPP amyloid formation in pancreas in 5 of 7 mice in each group, demonstrating that IAPP amyloid could be enhanced through homologous and heterologous seeding with higher efficiency for the former mechanism. Proximity Ligation assay was used for colocalization studies of IAPP and A beta in islet amyloid in type 2 diabetic patients and A beta deposits in brains of patients with Alzheimer disease. All reactivity was not detected in islet amyloid although islet beta cells express A beta PP and convertases necessary for A beta production. By contrast, IAPP and proIAPP were detected in cerebral and vascular A beta deposits, and presence of proximity Ligation signal at both locations showed that the peptides were <40 nm apart. It is not clear whether IAPP present in brain originates from pancreas or is Locally produced. Heterologous seeding between IAPP and All shown here may represent a molecular Link between type 2 diabetes and Alzheimer disease.

Place, publisher, year, edition, pages
2015. Vol. 185, no 3, 834-846 p.
National Category
Cell and Molecular Biology Immunology in the medical area
URN: urn:nbn:se:uu:diva-251443DOI: 10.1016/j.ajpath.2014.11.016ISI: 000350783800023PubMedID: 25700985OAI: oai:DiVA.org:uu-251443DiVA: diva2:807318
Available from: 2015-04-23 Created: 2015-04-17 Last updated: 2016-01-13Bibliographically approved
In thesis
1. Islet amyloid polypeptide (IAPP) in Type 2 diabetes and Alzheimer disease
Open this publication in new window or tab >>Islet amyloid polypeptide (IAPP) in Type 2 diabetes and Alzheimer disease
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The misfolding and aggregation of the beta cell hormone islet amyloid polypeptide (IAPP) into amyloid fibrils is the main pathological finding in islets of Langerhans in type 2 diabetes. Pathological assemblies of IAPP are cytotoxic and believed to contribute to the loss of insulin-producing beta cells. Changes in the microenvironment that could trigger the aggregation of IAPP are largely unknown. So is the possibility that islet amyloid can spread within or between tissues. The present thesis have explored the roles of glycosaminoglycan heparan sulfate (HS) and the novel anti-amyloid chaperone Bri2 BRICHOS domain in the assembly of IAPP amyloid and cytotoxic IAPP aggregates. Furthermore, cross-seeding as a molecular interaction between the observed connection of type 2 diabetes and Alzheimer disease has been examined.

The N-terminal region of IAPP was required for binding to HS structures and induction of binding promoted amyloid formation. Interference in the HS-IAPP interaction by heparanase degradation of HS or by introducing short, soluble HS-structure fragments reduced amyloid deposition in cultured islets. Cytotoxicity induced by extracellular, aggregating IAPP was mediated via interactions with cell-surface HS. This suggests that HS plays an important role in islet amyloid deposition and associated toxicity.

BRICHOS domain containing protein Bri2 was highly expressed in human beta cells and colocalized with IAPP intracellularly and in islet amyloid deposits. The BRICHOS domain effectively attenuated both IAPP amyloid formation and IAPP-induced cytotoxicity. These results propose Bri2 BRICHOS as a novel chaperone preventing IAPP aggregation in beta cells.

The intravenous injection of IAPP, proIAPP or amyloid-β (Aβ) fibrils enhanced islet amyloidosis in transgenic human IAPP mice, demonstrating that both homologous- and heterologous seeding of islet amyloid can occur in vivo. IAPP colocalized with Aβ in brain amyloid from AD patients, and AD patients diagnosed with T2D displayed increased proportions of neuritic plaques, the more pathogenic plaque subtype.

In conclusion, both IAPP amyloid formation and the cytotoxic effects of IAPP is dependent on interactions with HS whereas interactions with Bri2 BRICHOS is protective. Cross-seeding between Aβ and IAPP can occur in vivo and the two peptides colocalize in brain amyloid in AD patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 55 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1158
amyloid, IAPP, Abeta, type 2 diabetes, Alzheimer disease, BRICHOS, heparan sulfate, islet amyloid, amyloid plaques, seeding
National Category
Medical and Health Sciences Cell and Molecular Biology
Research subject
Medical Cell Biology
urn:nbn:se:uu:diva-265501 (URN)978-91-554-9400-1 (ISBN)
Public defence
2015-12-17, B21, BMC, Husargatan 3, Uppsala, 13:15 (English)
Available from: 2015-11-26 Created: 2015-10-30 Last updated: 2016-01-13

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Oskarsson, Marie E.Ingelsson, MartinWestermark, PerWestermark, Gunilla T.
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