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Oskarsson, Marie E.
Alternative names
Publications (7 of 7) Show all publications
Oskarsson, M. E., Hermansson, E., Wang, Y., Welsh, N., Presto, J., Johansson, J. & Westermark, G. (2018). The BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells. Proceedings of the National Academy of Sciences of the United States of America, 115(12), E2752-E2761
Open this publication in new window or tab >>The BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 12, p. E2752-E2761Article in journal (Refereed) Published
Abstract [en]

Aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils in islets of Langerhans is associated with type 2 diabetes, and formation of toxic IAPP species is believed to contribute to the loss of insulin-producing beta cells. The BRICHOS domain of integral membrane protein 2B (Bri2), a transmembrane protein expressed in several peripheral tissues and in the brain, has recently been shown to prevent fibril formation and toxicity of Aβ42, an amyloid-forming peptide in Alzheimer disease. In this study, we demonstrate expression of Bri2 in human islets and in the human beta-cell line EndoC-βH1. Bri2 colocalizes with IAPP intracellularly and is present in amyloid deposits in patients with type 2 diabetes. The BRICHOS domain of Bri2 effectively inhibits fibril formation in vitro and instead redirects IAPP into formation of amorphous aggregates. Reduction of endogenous Bri2 in EndoC-βH1 cells with siRNA increases sensitivity to metabolic stress leading to cell death while a concomitant overexpression of Bri2 BRICHOS is protective. Also, coexpression of IAPP and Bri2 BRICHOS in lateral ventral neurons of Drosophila melanogaster results in an increased cell survival. IAPP is considered to be the most amyloidogenic peptide known, and described findings identify Bri2, or in particular its BRICHOS domain, as an important potential endogenous inhibitor of IAPP aggregation and toxicity, with the potential to be a possible target for the treatment of type 2 diabetes.

Keywords
Bri2, BRICHOS, chaperone, IAPP, amyloid, islet amyloid, beta cells, type 2 diabetes
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-265483 (URN)10.1073/pnas.1715951115 (DOI)000427829500014 ()
Funder
Swedish Research CouncilSwedish Diabetes AssociationNovo NordiskErnfors Foundation
Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2018-06-01Bibliographically approved
Krizhanovskii, C., Fred, R. G., Oskarsson, M. E., Westermark, G. T. & Welsh, N. (2017). Addition of exogenous sodium palmitate increases the IAPP/insulin mRNA ratio via GPR40 in human EndoC-beta H1 cells. Upsala Journal of Medical Sciences, 122(3), 149-159
Open this publication in new window or tab >>Addition of exogenous sodium palmitate increases the IAPP/insulin mRNA ratio via GPR40 in human EndoC-beta H1 cells
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2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 3, p. 149-159Article in journal (Refereed) Published
Abstract [en]

Background: Enhanced IAPP production may contribute to islet amyloid formation in type 2 diabetes. The objective of this study was to determine the effects of the saturated fatty acid palmitate on IAPP levels in human beta-cells. Methods: EndoC-beta H1 cells and human islets were cultured in the presence of sodium palmitate. Effects on IAPP/insulin mRNA expression and secretion were determined using real-time qPCR/ELISA. Pharmacological activators and/or inhibitors and RNAi were used to determine the underlying mechanisms. Results: We observed that EndoC-beta H1 cells exposed to palmitate for 72 h displayed decreased expression of Pdx-1 and MafA and increased expression of thioredoxin-interacting protein (TXNIP), reduced insulin mRNA expression and glucose-induced insulin secretion, as well as increased IAPP mRNA expression and secretion. Further, these effects were independent of fatty acid oxidation, but abolished in response to GPR40 inhibition/downregulation. In human islets both a high glucose concentration and palmitate promoted increased IAPP mRNA levels, resulting in an augmented IAPP/insulin mRNA ratio. This was paralleled by elevated IAPP/insulin protein secretion and content ratios. Conclusions: Addition of exogenous palmitate to human beta-cells increased the IAPP/insulin expression ratio, an effect contributed to by activation of GPR40. These findings may be pertinent to our understanding of the islet amyloid formation process.

Keywords
Amyloid, fatty acids, insulin, islet amyloid polypeptide (IAPP), palmitate
National Category
Cell and Molecular Biology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-340975 (URN)10.1080/03009734.2017.1368745 (DOI)000414107800001 ()28980863 (PubMedID)
Available from: 2018-02-06 Created: 2018-02-06 Last updated: 2018-02-06Bibliographically approved
Krotee, P., Rodriguez, J. A., Sawaya, M. R., Cascio, D., Reyes, F. E., Shi, D., . . . Eisenberg, D. S. (2017). Atomic structures of fibrillar segments of hIAPP suggest tightly mated beta-sheets are important or cytotoxicity. eLIFE, 6
Open this publication in new window or tab >>Atomic structures of fibrillar segments of hIAPP suggest tightly mated beta-sheets are important or cytotoxicity
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2017 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 6Article in journal (Refereed) Published
Abstract [en]

hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic beta-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19-29 S20G, forms pairs of beta-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15-25 WT, forms non-toxic labile beta-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19-29 S20G may serve as a model for the toxic spine of hIAPP.

National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-316042 (URN)10.7554/eLife.19273 (DOI)000392186000001 ()
Funder
NIH (National Institute of Health), R01 AG029430
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2018-01-13Bibliographically approved
Westermark, G. T., Oskarsson, M., Andersson, A. & Westermark, P. (2015). Eighty years of research on islet amyloidosis in Uppsala. Upsala Journal of Medical Sciences, 120(2), 117-123
Open this publication in new window or tab >>Eighty years of research on islet amyloidosis in Uppsala
2015 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 2, p. 117-123Article in journal (Refereed) Published
Keywords
Alzheimer's disease, amyloid, IAPP, senile amyloidosis, type 2 diabetes
National Category
Other Medical Sciences not elsewhere specified
Identifiers
urn:nbn:se:uu:diva-255284 (URN)10.3109/03009734.2015.1037032 (DOI)000353920500009 ()25903284 (PubMedID)
Available from: 2015-06-22 Created: 2015-06-15 Last updated: 2017-12-04Bibliographically approved
Oskarsson, M. E., Singh, K., Wang, J., Vlodavsky, I., Li, J.-p. & Westermark, G. T. (2015). Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis. Journal of Biological Chemistry, 290(24), 15121-15132
Open this publication in new window or tab >>Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis
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2015 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 24, p. 15121-15132Article in journal (Refereed) Published
Abstract [en]

Deposition of beta cell toxic islet amyloid is a cardinal finding in type 2 diabetes. In addition to the main amyloid component islet amyloid polypeptide (IAPP), heparan sulfate proteoglycan is constantly present in the amyloid deposit. Heparan sulfate (HS) side chains bind to IAPP, inducing conformational changes of the IAPP structure and an acceleration of fibril formation. We generated a double-transgenic mouse strain (hpa-hIAPP) that overexpresses human heparanase and human IAPP but is deficient of endogenous mouse IAPP. Culture of hpa-hIAPP islets in 20 mM glucose resulted in less amyloid formation compared with the amyloid load developed in cultured islets isolated from littermates expressing human IAPP only. A similar reduction of amyloid was achieved when human islets were cultured in the presence of heparin fragments. Furthermore, we used CHO cells and the mutant CHO pgsD-677 cell line (deficient in HS synthesis) to explore the effect of cellular HS on IAPP-induced cytotoxicity. Seeding of IAPP aggregation on CHO cells resulted in caspase-3 activation and apoptosis that could be prevented by inhibition of caspase-8. No IAPP-induced apoptosis was seen in HS-deficient CHO pgsD-677 cells. These results suggest that beta cell death caused by extracellular IAPP requires membrane-bound HS. The interaction between HS and IAPP or the subsequent effects represent a possible therapeutic target whose blockage can lead to a prolonged survival of beta cells.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-257645 (URN)10.1074/jbc.M114.631697 (DOI)000356177300027 ()25922077 (PubMedID)
Funder
Swedish Cancer Society, 120762
Available from: 2015-07-09 Created: 2015-07-06 Last updated: 2017-12-04Bibliographically approved
Oskarsson, M. E., Paulsson, J. F., Schultz, S. W., Ingelsson, M., Westermark, P. & Westermark, G. T. (2015). In Vivo Seeding and Cross-Seeding of Localized Amyloidosis A Molecular Link between Type 2 Diabetes and Alzheimer Disease. American Journal of Pathology, 185(3), 834-846
Open this publication in new window or tab >>In Vivo Seeding and Cross-Seeding of Localized Amyloidosis A Molecular Link between Type 2 Diabetes and Alzheimer Disease
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2015 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 185, no 3, p. 834-846Article 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.

National Category
Cell and Molecular Biology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-251443 (URN)10.1016/j.ajpath.2014.11.016 (DOI)000350783800023 ()25700985 (PubMedID)
Available from: 2015-04-23 Created: 2015-04-17 Last updated: 2018-01-11Bibliographically approved
Oskarsson, M. (2015). Islet amyloid polypeptide (IAPP) in Type 2 diabetes and Alzheimer disease. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
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. p. 55
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1158
Keywords
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
Identifiers
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)
Opponent
Supervisors
Available from: 2015-11-26 Created: 2015-10-30 Last updated: 2018-01-10
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