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  • 1. Alvarsson, M
    et al.
    Sundkvist, G
    Lager, I
    Henricsson, M
    Berntorp, K
    Fernqvist-Forbes, E
    Steen, L
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Westermark, P
    Orn, T
    Beneficial effects of insulin versus sulphonylurea on insulin secretion and metabolic control in recently diagnosed type 2 diabetic patients2003In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 26, no 8, p. 2231-2237Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE - To evaluate whether treatment with insulin in recently diagnosed type 2 diabetes is advantageous compared with glibenclamide treatment. RESEARCH DESIGN AND METHODS - ▀-Cell function, glycemic control, and quality of life were monitored over 2 years in 39 patients with islet cell antibody-negative type 2 diabetes diagnosed 0-2 years before inclusion in a Swedish multicenter randomized clinical trial. Patients were randomized to either two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide (3.5-10.5 mg daily). C-peptide-glucagon tests were performed yearly in duplicate after 2-3 days of temporary withdrawal of treatment. RESULTS - After 1 year the glucagon-stimulated C-peptide response was increased in the insulin-treated group by 0.14 ▒ 0.08 nmol/l, whereas it was decreased by 0.12 ▒ 0.08 nmol/l in the glibenclamide group, P < 0.02 for difference between groups. After 2 years, fasting insulin levels were higher after treatment withdrawal in the insulin-treated versus the glibenclamide-treated group (P = 0.02). HbA1c levels decreased significantly during the first year in both groups, however, at the end of the second year, HbA1c had deteriorated in the glibenclamide group (P < 0.01), but not in the insulin-treated group. The difference in evolution of HbA1c during the second year was significant between groups, P < 0.02 A questionnaire indicated no difference in well-being related to treatment. CONCLUSIONS - Early insulin versus glibenclamide treatment in type 2 diabetes temporarily prolongs endogenous insulin secretion and promotes better metabolic control.

  • 2. Alvarsson, M
    et al.
    Sundkvist, G
    Lager, I
    Henricsson, M
    Berntorp, K
    Forbes, E
    Steen, L
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Orn, T
    Grill, V
    Different effects of withdrawal of insulin or glibenclamide treatment on beta cell function in recently diagnosed Type 2 diabetic patients.2003In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 46, p. 798-Conference paper (Other academic)
  • 3.
    Anderson, Emma S.
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Bjartmar, Carl
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Eriksson, Cecilia
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Hildebrand, Claes
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Developing chicken oligodendrocytes express the type IV oligodendrocyte marker T4-O in situ, but not in vitro2000In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 284, no 1-2, p. 21-24Article in journal (Refereed)
    Abstract [en]

    Accumulating data suggest that the oligodendrocyte population includes morphological and biochemical subtypes. We recently reported that a polyclonal antiserum against an unknown antigen, the T4-O molecule, labels a subpopulation of chicken oligodendrocytes, obviously representing the type IV variety of Del Rio Hortega. The present study examines the developmental expression of the T4-O molecule in situ and in vitro. The results show that T4-O immunoreactive cells first appear at E15 in the ventral funiculus. But, oligodendrocytes cultured in vitro with or without neurones do not develop a T4-O immunoreactivity. We conclude that oligodendrocytes in the spinal cord of chicken embryos first express the T4-O molecule some time after onset of myelination, and that the T4-O immunoreactive phenotype does not develop in vitro.

  • 4.
    Anderson, Emma S.
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Bjartmar, Carl
    Department of Neurosciences, Lerner Research Institue, Cleveland Clinic Foundation, Cleveland, Ohio.
    Westermark, Gunilla
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Hildebrand, Claes
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Molecular heterogeneity of oligodendrocytes in chicken white matter1999In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 27, no 1, p. 15-21Article in journal (Refereed)
    Abstract [en]

    The classical studies by Del Rio Hortega (Mem. Real. Soc. Espan. Hist. Nat. 14:40–122, 1928) suggest that the oligodendrocyte population includes four morphological subtypes. Recent data from the cat and the rat show that the anatomy of oligodendrocytes related to early myelinating prospective large fibers differs from that of oligodendrocytes related to late myelinating prospective small fibers. After application of a polyclonal antiserum to cryostat sections from the chicken CNS, we noted that glial cells in the spinal cord white matter had become labeled. Analysis of the occurrence and cellular localization of this immunoreactivity—the T4-O immunoreactivity—in the CNS of the adult chicken showed that T4-O immunoreactive cells are enriched in the ventral funiculus and superficially in the lateral funiculus of the spinal cord, where they are co-localized with large fibers. Double staining with T4-O antiserum and anti-GFAP or the lectin BSI-B4 revealed that T4-O immunoreactive cells are not astrocytes or microglia. Staining with anti-HSP108, a general marker for avian oligodendrocytes, showed that T4-O immunoreactivity defines an oligodendroglial subpopulation. A search for T4-O immunoreactivity in spinal cord white matter of some other vertebrates revealed that T4-O immunoreactive cells are not present in sections from fish, frog, turtle, rat, and rabbit spinal cord white matter. These results suggest the presence of a fiber size-related molecular heterogeneity among chicken white matter oligodendrocytes.

  • 5.
    Andersson, Arne
    et al.
    Uppsala University.
    Bohman, Sara
    Uppsala University.
    Borg, L A Hakan
    Uppsala University.
    Paulsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Schultz, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Per
    Uppsala University.
    Amyloid Deposition in Transplanted Human Pancreatic Islets: A Conceivable Cause of Their Long-Term Failure2008In: EXPERIMENTAL DIABETES RESEARCH, ISSN 1687-5214, Vol. 2008, no 562985Article in journal (Refereed)
    Abstract [en]

    Following the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the beta-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.

  • 6. Bergstrom, J
    et al.
    Murphy, C
    Eulitz, M
    Weiss, DT
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Solomon, A
    Westermark, P
    An additional apolipoprotein in ATTR-amyloid2001In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 8, p. 32-33Conference paper (Other academic)
  • 7. Bergström, Joakim
    et al.
    Murphy, Charles
    Eulitz, Manfred
    Weiss, Deborah
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Solomon, Alan
    Westermark, Per
    Codeposition of apolipoprotein A-IV and transthyretin in senile systemic (ATTR) amyloidosis2001In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 285, no 4, p. 903-908Article in journal (Refereed)
    Abstract [en]

    Protein material was extracted from amyloid-rich sections of formalin-fixed and paraffin-embedded heart tissue from an individual with senile systemic amyloidosis, known to contain wild-type transthyretin as major amyloid fibril protein. Amino acid sequence analysis of tryptic peptides of this material revealed in addition to transthyretin sequences, also amino acid sequence corresponding to an N-terminal fragment of apolipoprotein A-IV. In immunohistochemistry, an antiserum to a synthetic apolipoprotein A-IV peptide labeled amyloid specifically. This peptide formed spontaneously amyloid-like fibrils in vitro and enhanced fibril formation from wild-type transthyretin. We conclude that several apolipoproteins, including apolipoprotein A-IV, may be important minor amyloid constituents, promoting fibril formation.

  • 8.
    Carlsson, Jenny
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics . Linköping University, The Institute of Technology.
    Gullstrand, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    An indirect competitive immunoassay for insulin autoantibodies based on surface plasmon resonance2008In: Biosensors and Bioelectronics, ISSN 0956-5663, Vol. 24, no 4, p. 876-881Article in journal (Refereed)
    Abstract [en]

    We have developed a sensitive and specific method based on surface plasmon resonance (SPR) for detection of insulin autoantibodies (IAA) in serum samples from individuals at high risk of developing type 1 diabetes (T1D). When measuring trace molecules in undiluted sera with label-free techniques like SPR, non-specific adsorption of matrix proteins to the sensor surface is often a problem, since it causes a signal that masks the analyte response. The developed method is an indirect competitive immunoassay designed to overcome these problems. Today, IAA is mainly measured in radio immunoassays (RIAs), which are time consuming and require radioactively labeled antigen. With our SPR-based immunoassay the overall assay time is reduced by a factor of >100 (4 days to 50 min), while sensitivity is maintained at a level comparable to that offered by RIA.

  • 9.
    Carlsson, Jenny
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, The Institute of Technology.
    Gullstrand, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Determination of insulin autoantibodies using surface plasmon resonance: A screening study of newly diagnosed type 1 diabetes patients2008Manuscript (preprint) (Other academic)
    Abstract [en]

    We have investigated the screening potential of a surface plasmon resonance (SPR)-based indirectcompetitive immunoassay for quantification of insulin autoantibodies (IAA) in sera from childrennewly diagnosed with type 1 diabetes (T1D), using a radioimmunoassay (RIA) as reference technique.The two methods agreed well with respect to sample classification of 54 sera from newly diagnosedT1D children and 32 reference sera from non-diabetic children. Interestingly, five samples from newlydiagnosed T1D patients classified as IAA-negative according to RIA were IAA-positive with the SPRbasedassay, suggesting that the SPR-based assay might provide a higher sensitivity than the referenceRIA. However, 14 percent of the analyzed samples (five samples from non-diabetics and seven fromnewly diagnosed T1D patients) gave rise to anomalously high and easily distinguishable responses withthe SPR-based method, precluding IAA-quantification. A considerable part of the paper is devoted to adiscussion of possible causes of these anomalous responses. They were not due to temporary changesin the status of the patients, such as infections at the time of sampling, and also not related tocomplement activation. It is speculated whether a plausible explanation should instead be sought in theexistence of anti-idiotypic antibodies to IAA.

  • 10.
    Carlsson, Jonas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Vahdat Shariatpanahi, Aida
    Schultz, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    A folding study on IAPP (Islet Amyloid Polypeptide) using molecular dynamics simulationsManuscript (preprint) (Other academic)
    Abstract [en]

    Amyloidosis is the largest group among the protein misfolding diseases, and includes well known diseases such as Alzheimer’s disease and type 2 diabetes. In the latter, islet amyloid is present in the pancreas in almost all individuals. Today, more than 25 different proteins have been isolated from amyloid deposits in human. Even though these proteins differ in size, charge and sequence they all have the capacity to assemble in to fibrillar structures with inseparable morphological appearance. Therefore, it can be assumed that the fibril process is based upon principles that are general for all proteins and knowledge derived from one protein can be used for other amyloid proteins. In this paper, we study the process of amyloid formation in parts of islet amyloid polypeptide (residues 18-29 and 11-37) by analyzing mutations using three different in silico methods. Finally, we use the methods to predict the amyloidogenic properties of the native IAPP and 16 variants thereof and compare the result with in vitro measurements. Using a consensus prediction of the three methods we managed to correctly classify all but two peptides. We have also given further evidence to the importance of S28P for inhibiting amyloid fibre formation, found evidence for antiparallel stacking, and identified important regions for beta sheet stability.

  • 11.
    Chisalita, Simona Ioana
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Lindström, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Eson Jennersjö, Pär
    Borensberg Health Centre, Linköping.
    Paulsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Differential lipid profile and hormonal response in type 2 diabetes by exogenous insulin aspart versus the insulin secretagogue repaglinide, at the same glycemic control2009In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 46, no 1, p. 35-42Article in journal (Refereed)
    Abstract [en]

    Our aim was to study, at the same glycemic control, how treatment with either the insulin secretagogue repaglinide or exogenous insulin aspart affects endogenous insulin secretion, plasma insulin and IAPP (islet amyloid polypeptide) levels, GH-IGF (growth hormone-insulin-like growth factor) axis and plasma lipoprotein concentrations in patients with type 2 diabetes. Five patients, age 65.0 +/- A 4.1 years (mean +/- A SE), body weight 82.5 +/- A 5.0 kg, BMI (body mass index) 27.7 +/- A 1.5 kg/m(2) were treated for 10 weeks with repaglinide or insulin aspart in a randomized, cross-over study. At the end of each treatment a 24-h metabolic profile was performed. Blood glucose, C-peptide, free human insulin, free total (human and analogue) insulin, proinsulin, IAPP, IGF-I, IGFBP-1 (IGF binding protein-1), GHBP (growth hormone binding protein) and plasma lipoprotein concentrations were measured. Similar 24-h blood glucose profiles were obtained with repaglinide and insulin aspart treatment. During the repaglinide treatment, the meal related peaks of C-peptide and free human insulin were about twofold higher than during treatment with insulin aspart. Proinsulin, GHBP were higher and IAPP levels tended to be higher during repaglinide compared to insulin aspart. Postprandial plasma total cholesterol, triglycerides and apolipoprotein B concentrations were higher on repaglinide than on insulin aspart treatment. Our results show that, at the same glycemic control, treatment with exogenous insulin aspart in comparison with the insulin secretagogue repaglinide result in a lower endogenous insulin secretion, and a tendency towards a less atherogenic postprandial lipid profile.

  • 12. Feng, Wang
    et al.
    Adrian, TE
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Ding, X
    Gasslander, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Permert, Johan
    Islet amyloid polypeptide tonally inhiits beta-, alpha-, and delta-cell secretion in isolated rat pancreatic islets.1999In: American journal of physiology, ISSN 0002-9513, Vol. 276, p. 19-24Article in journal (Refereed)
  • 13. Feng, Wang
    et al.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Gasslander, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Permert, Johan
    Effect of islet amyloid polypeptide on somatostatin inhibition of insulin secretion from isolated rat pancreatic islets.1999In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 72, p. 61-67Article in journal (Refereed)
  • 14. Hull, Rebecca L
    et al.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Westermark, Per
    Kahn, Steven E
    Islet amyloid: A critical entity in the pathogenesis of type 2 diabetes2004In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 89, no 8, p. 3629-3643Article in journal (Refereed)
    Abstract [en]

    Islet amyloid deposition is a pathogenic feature of type 2 diabetes, and these deposits contain the unique amyloidogenic peptide islet amyloid polypeptide. Autopsy studies in humans have demonstrated that islet amyloid is associated with loss of β-cell mass, but a direct role for amyloid in the pathogenesis of type 2 diabetes cannot be inferred from such studies. Animal studies in both spontaneous and transgenic models of islet amyloid formation have shown that amyloid forms in islets before fasting hyperglycemia and therefore does not arise merely as a result of the diabetic state. Furthermore, the extent of amyloid deposition is associated with both loss of β-cell mass and impairment in insulin secretion and glucose metabolism, suggesting a causative role for islet amyloid in the islet lesion of type 2 diabetes. These animal studies have also shown that β-cell dysfunction seems to be an important prerequisite for islet amyloid formation, with increased secretory demand from obesity and/or insulin resistance acting to further increase islet amyloid deposition. Recent in vitro studies suggest that the cytotoxic species responsible for islet amyloid-induced β-cell death are formed during the very early stages of islet amyloid formation, when islet amyloid polypeptide aggregation commences. Interventions to prevent islet amyloid formation are emerging, with peptide and small molecule inhibitors being developed. These agents could thus lead to a preservation of β-cell mass and amelioration of the islet lesion in type 2 diabetes.

  • 15.
    Häggqvist, Bo
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Näslund, J
    Sletten, K
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Mucchiano, G
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Tjernberg, LO
    Nordstedt, C
    Engström, U
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Medin: an integral fragment of aortic smooth muscle cell-produced lactadherin forms the most common form of human amyloid. 1999In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 96, p. 8669-8674Article in journal (Refereed)
  • 16.
    Johan, Katarzyna
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Engström, Ulla
    Ludwig Institute for Cancer Research, Uppsala Branch, Uppsala, Sweden.
    Gustavsson, Åsa
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils1998In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, no 5, p. 2558-2563Article in journal (Refereed)
    Abstract [en]

    Amyloid protein A (AA) amyloidosis is a consequence of some long-standing inflammatory conditions, and subsequently, an N-terminal fragment of the acute phase protein serum AA forms β-sheet fibrils that are deposited in different tissues. It is unknown why only some individuals develop AA amyloidosis. In the mouse model, AA amyloidosis develops after ≈25 days of inflammatory challenge. This lag phase can be shortened dramatically by administration of a small amount of amyloid extract containing an as yet undefined amyloid-enhancing factor. In the present study, we show that preformed amyloid-like fibrils made from short synthetic peptides corresponding to parts of several different amyloid fibril proteins exert amyloidogenic enhancing activity when given i.v. to mice at the induction of inflammation. We followed i.v. administered, radiolabeled, heterologous, synthetic fibrils to the lung and to the perifollicular area in the spleen and found that new AA–amyloid fibrils developed on these preformed fibrils. Our findings thus show that preformed, synthetic, amyloid-like fibrils have an in vivo nidus activity and that amyloid-enhancing activity may occur, at least in part, through this mechanism. Our findings also show that fibrils of a heterologous chemical nature exert amyloid-enhancing activity.

  • 17. Larsson, Annika
    et al.
    Söderberg, Linda
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Sletten, Knut
    Engström, Ulla
    Tjernberg, Lars O
    Näslund, Jan
    Westermark, Per
    Unwinding fibril formation of medin, the peptide of the most common form of human amyloid2007In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 361, no 4, p. 822-828Article in journal (Refereed)
    Abstract [en]

    Medin amyloid affects the medial layer of the thoracic aorta of most people above 50 years of age. The consequences of this amyloid are not completely known but the deposits may contribute to diseases such as thoracic aortic aneurysm and dissection or to the general diminished elasticity of blood vessels seen in elderly people. We show that the 50-amino acid residue peptide medin forms amyloid-like fibrils in vitro. With the use of Congo red staining, Thioflavin T fluorescence, electron microscopy, and a solid-phase binding assay on different synthetic peptides, we identified the last 18-19 amino acid residues to constitute the amyloid-promoting region of medin. We also demonstrate that the two C-terminal phenylalanines, previously suggested to be of importance for amyloid formation, are not required for medin amyloid formation.

  • 18.
    Lundberg, Erik
    et al.
    Umeå University.
    Olofsson, Anders
    Umeå University.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Sauer-Eriksson , A Elisabeth
    Umeå University.
    Stability and fibril formation properties of human and fish transthyretin, and of the Escherichia coli transthyretin-related protein2009In: FEBS JOURNAL, ISSN 1742-464X , Vol. 276, no 7, p. 1999-2011Article in journal (Refereed)
    Abstract [en]

    Human transthyretin (hTTR) is one of several proteins known to cause amyloid disease. Conformational changes in its native structure result in aggregation of the protein, leading to insoluble amyloid fibrils. The transthyretin (TTR)-related proteins comprise a protein family of 5-hydroxyisourate hydrolases with structural similarity to TTR. In this study, we tested the amyloidogenic properties, if any, of sea bream TTR (sbTTR) and Escherichia coli transthyretin-related protein (ecTRP), which share 52% and 30% sequence identity, respectively, with hTTR. We obtained filamentous structures from all three proteins under various conditions, but, interestingly, different structures displayed different tinctorial properties. hTTR and sbTTR formed thin, curved fibrils at low pH (pH 2-3) that bound thioflavin-T (thioflavin-T-positive) but did not stain with Congo Red (CR) (CR-negative). Aggregates formed at the slightly higher pH of 4.0-5.5 had different morphology, displaying predominantly amorphous structures. CR-positive material of hTTR was found in this material, in agreement with previous results. ecTRP remained soluble at pH 2-12 at ambient temperatures. By raising of the temperature, fibril formation could be induced at neutral pH in all three proteins. Most of these temperature-induced fibrils were thicker and straighter than the in vitro fibrils seen at low pH. In other words, the temperature-induced fibrils were more similar to fibrils seen in vivo. The melting temperature of ecTRP was 66.7 degrees C. This is approximately 30 degrees C lower than the melting temperatures of sbTTR and hTTR. Information from the crystal structures was used to identify possible explanations for the reduced thermostability of ecTRP.

  • 19.
    Lundmark, Katarzyna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Vahdat Shariatpanahi, Aida
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Westermark, P
    Uppsala University.
    Westermark, Gunilla T
    Uppsala University.
    Depletion of macrophages influences amyloid deposition in spleen in AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS, vol 17, issue , pp 115-1152010In: AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS, Informa Healthcare , 2010, Vol. 17, p. 115-115Conference paper (Refereed)
    Abstract [en]

    n/a

  • 20.
    Lundmark, Katarzyna
    et al.
    Division of Pathology, Karolinska University Hospital, Huddinge, Sweden.
    Westermark, Gunilla
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Olsén, Arne
    Department of Clinical Immunology, Göteborg University, Göteborg, Sweden.
    Westermark, Per
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism2005In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, no 17, p. 6098-6102Article in journal (Refereed)
    Abstract [en]

    Secondary, or amyloid protein A (AA), amyloidosis is a complication of chronic inflammatory diseases, both infectious and noninfectious. AA constitutes the insoluble fibrils, which are deposited in different organs, and is a major N-terminal part of the acute phase protein serum AA. It is not known why only some patients with chronic inflammation develop AA amyloidosis. Nucleation is a widely accepted mechanism in amyloidogenesis. Preformed amyloid-like fibrils act as nuclei in amyloid fibril formation in vitro, and AA amyloid fibrils and synthetic amyloid-like fibrils also may serve as seed for fibril formation in vivo. In addition to amyloid fibrils, there is a variety of similar nonmammalian protein fibrils with β-pleated structure in nature. We studied three such naturally occurring protein fibrils: silk from Bombyx mori, Sup35 from Saccharomyces cerevisiae, and curli from Escherichia coli. Our results show that these protein fibrils exert amyloid-accelerating properties in the murine experimental AA amyloidosis, suggesting that such environment factors may be important risk factors in amyloidogenesis.

  • 21.
    Lundmark, Katarzyna
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lindquist, Susan
    Howard Hughes Medical Institute, University of Chicago, Il, USA.
    Westermark, Per
    Department of Genetics and Pathology, Uppsala University, Sweden.
    Naturally occurring fibrillar proteins can induce AA amyloidosis by a prion-like mechanismManuscript (preprint) (Other academic)
    Abstract [en]

    Experimental AA amyloidosis, where the acute phase protein serum AA (SAA) forms amyloid fibrils, can be induced in mice provoked with inflannnatmy challenge. The time for development of amyloid is dramatically shortened when the animals concomitantly receive extract of a tissue from another mouse with amyloid 1-3. The active elusive principle has been named Amyloid Enhancing Factor (AEF) and experimental secondary amyloidosis was supposed to be a nucleation dependent process. The nature of the nucleus, however, was unknown for a long time. Our studies with synthetic amyloid-like fibrils made frmn short amyloidogenic pep tides instead of AEF 4, 5, indicate that the amyloid fibrils theruselves may act as nuclei for fibril formation (Fig. 1a). Here we present the enhanced development of AA -amyloidosis by naturally occurring amyloid-like protein fibrils.

  • 22.
    Lundmark, Katarzyna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Murphy, Charles L.
    Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, TN 37996, USA.
    Solomon, Alan
    Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, TN 37996, USA.
    Westermark, Per
    Department of Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
    Transmissibility of systemic amyloidosis by a prion-like mechanism2002In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, no 10, p. 6979-6984Article in journal (Refereed)
    Abstract [en]

    The generation of amyloid fibrils from an amyloidogenic polypeptide occurs by a nucleation-dependent process initiated in vitro by seeding the protein solution with preformed fibrils. This phenomenon is evidenced in vivo by the fact that amyloid protein A (AA) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an i.v. injection of protein extracted from AA amyloid-laden mouse tissue. Heretofore, the chemical nature of this “amyloid enhancing factor” (AEF) has not been definitively identified. Here we report that the active principle of AEF extracted from the spleen of mice with silver nitrate-induced AA amyloidosis was identified unequivocally as the AA fibril itself. Further, we demonstrated that this material was extremely potent, being active in doses <1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. Our studies have provided evidence that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.

  • 23.
    Ma, Z
    et al.
    Linkoping Univ Hosp, Div Mol & Immunol Pathol, S-58185 Linkoping, Sweden Linkoping Univ Hosp, Div Cell Biol, S-58185 Linkoping, Sweden.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Effects of free fatty acids (FFAs) on polymerization of islet amyloid polypeptide (IAPP) in vitro and on amyloid fibril formation in cultivated isolated islets of transgenic mice2002In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 45, p. 440-Conference paper (Other academic)
  • 24.
    Ma, Zhi
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Li, Z.-C.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Engström, U.
    Ludwig Institute of Cancer Research, Uppsala Branch, Uppsala, Sweden.
    Westermark, P.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Altered immunoreactivity of islet amyloid polypeptide (IAPP) may reflect major modifications of the IAPP molecule in amyloidogenesis1997In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 40, no 7, p. 793-801Article in journal (Refereed)
    Abstract [en]

    We have developed a mouse monoclonal antibody against rat/mouse islet amyloid polypeptide (IAPP). The antibody recognises an epitope in the N-terminal part of the molecule, which is conserved between different species. The antibody immunohistochemically labelled beta cells in normal islets of most different mammalian species including man and in one avian species. Previous immunohistochemical studies of human pancreatic tissue from individuals with non-insulin-dependent diabetes mellitus (NIDDM) have revealed a paradoxical and unexplained lack of IAPP immunoreactivity in beta cells close to amyloid in spite of the presence of IAPP mRNA. In contrast to these findings we show that the newly developed monoclonal IAPP antibody strongly labels such beta cells while islet amyloid deposits which are labelled by polyclonal antisera do not bind the monoclonal antibody. These findings with the polyclonal antisera and the monoclonal antibody indicate that IAPP undergoes one or several structural changes during the amyloidogenesis. Knowledge of these structural changes that may include abnormal folding or chemical modification of IAPP is probably important for the understanding of the amyloidogenesis and the pathogenesis of the islet lesion in NIDDM.

  • 25.
    Ma, Zhi
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Sakagashira, S.
    First Department of Medicine, Wakayama University of Medical Science, Kagawa Medical University, Japan.
    Sanke, T.
    First Department of Medicine, Wakayama University of Medical Science, Kagawa Medical University, Japan.
    Gustavsson, Å
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Sakamoto, H.
    Department of Pathology, Kagawa Medical University, Japan.
    Engstrom, U.
    Ludwig Institute of Cancer Research, Uppsala Branch, Uppsala University, Uppsala, Sweden.
    Nanjo, K.
    First Department of Medicine, Wakayama University of Medical Science, Kagawa Medical University, Japan.
    Westermark, P.
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Enhanced in vitro production of amyloid-like fibrils from mutant (S20G) islet amyloid polypeptide2001In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 8, no 4, p. 242-249Article in journal (Refereed)
    Abstract [en]

    Islet amyloid polypeptide (IAPP, “amylin”) is the amyloid-fibril-forming polypeptide in the islets of Langerhans associated with type 2 diabetes mellitus. A missense mutation in the IAPP gene associated with early-onset type 2 diabetes has been identified in the Japanese population. This mutation results in a glycine for serine substitution at position 20 of the mature IAPP molecule. Whether or not formation of islet amyloid with resulting destruction of islet tissue is the cause of this diabetes is yet not known. The present in vitro study was performed in order to investigate any influence of the amino acid substitution on the fibril formation capacity. Synthetic full-length wild type (lAPPwt) and mutant (IAPPS20G) as well as corresponding truncated peptides (position 18-29) were dissolved in dimethylsulfoxide (DMSO) or in 10% acetic acid at a concentration of 10 mg/mL and their fibril forming capacity was checked by Congo red staining, electron microscopy, a Congo red affinity assay and Thioflavine T fluorometric assay. It was found that full-length and truncated IAPPS20G both formed more amyloid-like fibrils and did this faster compared to IAPPwt. The fibril morphology differed slightly between the preparations. Conclusion: The amino acid substitution (S20G) is situated close to the region of the IAPP molecule implicated in the IAPP fibrillogenesis. The significantly increased formation of amyloid-like fibrils by IAPPS20G is highly interesting and may be associated with an increased islet amyloid formation in vivo and of fundamental importance in the pathogenesis of this specific form of diabetes.

  • 26.
    Ma, Zhi
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Effects of free fatty acid on polymerization of islet amyloid polypeptide (IAPP) in vitro and on amyloid fibril formation in cultivated isolated islets of transgenic mice overexpressing human IAPP2002In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 8, no 12, p. 863-868Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Islet amyloid polypeptide (IAPP) is deposited as amyloid in the islets of Langerhans in type 2 diabetes. The mechanism behind the formation of the cytotoxic fibrils is unknown. Islet amyloid develops in a mouse IAPP null mouse strain that expresses human IAPP (+hIAPP/-mIAPP) after 9 months on a high-fat diet. Herein we investigate the effect that individual free fatty acids (FFAs) exert on formation of amyloid-like fibrils from synthetic IAPP and the effects of FFAs on IAPP polymerization in +hIAPP/-mIAPP islets cultivated in vitro.

    MATERIALS AND METHODS: In the study myristic acid, palmitic acid, stearic acid, oleic acid, and linoleic acid were used together with albumin. Thioflavin T (Th T) assay was used for quantification of amyloid-like fibrils. Islets were isolated from the +hIAPP/-mIAPP transgenic strain and cultured in the presence of the FFAs for 2 days. Immuno-electron microscopy was used for evaluation.

    RESULTS: The Th T assay showed that all studied FFAs potentiated fibril formation but that myristic acid revealed the highest capacity. In some cells from cultured islets, intragranular aggregates were present. These aggregates had a filamentous appearance and labeled with antibodies against IAPP. In some cells cultured in the presence of linoleic acid, large amounts of intracellular amyloid were present. Earlier, this has not been observed after such a short incubation period.

    CONCLUSIONS: Our studies suggest that FFAs can potentiate amyloid formation in vitro, probably without being integrated in the fibril. Cultivation of +hIAPP/-mIAPP transgenic mouse islets with FFAs results in altered morphology of the secretory granules with appearance of IAPP- immunoreactive fibrillar material. We suggest that such fibrillar material may seed extracellular amyloid formation after exocytosis.

  • 27.
    Ma, Zhi
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Johnsson, Kenneth H.
    Department of Veterinary Patho Biology, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, 55108, USA.
    O'Brien, Timothy D.
    Department of Veterinary Diagnostic Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, 55108, USA .
    Westermark, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Quantitative immunohistochemical analysis of islet amyloid polypeptide (IAPP) in normal, impaired glucose tolerant, and diabetic cats1998In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 5, no 4, p. 255-261Article in journal (Refereed)
    Abstract [en]

    Islet amyloid polypeptide (IAPP, “amylin”) has been proposed as having important roles in the pathogenesis of type 2 diabetes mellitus via its biological activity and by forming islet amyloid. The domestic cat develops a type of diabetes that closely resembles type 2 diabetes in humans, including the frequent formation of islet amyloid deposits in the impaired glucose tolerant (IGT) and diabetic state. With the aid of computerized image analysis and immuno-histochemistry, we examined the IAPP and insulin content inpancreatic islets of normal, IGT and diabetic cats. IAPP immunoreactivity in beta cells from IGT cats was significantly stronger (p < 0.01) as compared with cells from normal cats, while the insulin labelling strength was unchanged. Overtly diabetic cats were usually almost devoid of beta cells. As in humans, cellular IAPP but not IAPP in islet amyloid deposits was labelled by the newly developed monoclonal antibody to IAPP 4A5, thus providing further evidence that IAPP is modified by a yet unknown mechanism during the amyloidogenic process. The study provides evidence that an increased beta cell storage of IAPP independent of insulin may be an important factor in the early phase of the development of islet amyloid in this form of diabetes.

  • 28.
    Ma, Zhi
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, P.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Amyloid in Human Islets of Langerhans: Immunologic Evidence That Islet Amyloid Polypeptide Is Modified in Amyloidogenesis2000In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 21, no 2, p. 212-218Article in journal (Refereed)
    Abstract [en]

    Amyloid derived from the beta-cell product islet amyloid polypeptide (IAPP) has been implicated for a beta-cell lesion in Type II diabetes mellitus. The pathogenesis of islet amyloid is poorly understood, and in addition to an amyloidogenic IAPP molecule and possibly increased concentration of IAPP, other unknown factors seem to be included. It was shown previously that polyclonal rabbit IAPP antisera label beta cells close to amyloid only weakly. Whether this lack of immunoreactivity depends on lack of IAPP or on hidden epitopes is in question. In the present study, we show that the IAPP immunoreactivity of these beta cells is possible to retrieve. On the other hand, the monoclonal IAPP antibody 4A5, which labels IAPP in beta cells, does not label IAPP in its native amyloid form. We show evidence that this lack of immunoreactivity is not dependent on conformational change of the IAPP molecules in the amyloidogenesis but is likely owing to glycation of IAPP in human islet amyloid deposits.

  • 29. McAdam, KPWJ
    et al.
    Raynes, JG
    Alpers, MP
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Amyloidosis: a global problem common in Papua New Guinea. 1999In: Papau New Guinea Medical Journal, ISSN 0031-1480, Vol. 39, p. 284-296Article in journal (Refereed)
  • 30.
    Nilsson, M.
    et al.
    Department of Clinical Chemistry, University Hospital, S-22185 Lund, Sweden.
    Wang, X.
    Department of Clinical Chemistry, University Hospital, S-22185 Lund, Sweden.
    Rodziewicz-Motowidlo, S.
    Department of Organic Chemistry, Faculty of Chemistry, University of Gdansk, J. Sobieskiego 18, 80-952 Gdansk, Poland.
    Janowski, R.
    Department of Crystallography, A. Mickiewicz University, Polish Academy of Sciences, Grunwaldzka 6, 60-780 Poznan, Poland.
    Lindstrom, V.
    Lindström, V., Department of Clinical Chemistry, University Hospital, S-22185 Lund, Sweden.
    Onnerfjord, P.
    Önnerfjord, P., Dept. of Cell and Molecular Biology, University of Lund, S-22184 Lund, Sweden.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Grzonka, Z.
    Department of Organic Chemistry, Faculty of Chemistry, University of Gdansk, J. Sobieskiego 18, 80-952 Gdansk, Poland.
    Jaskolski, M.
    Department of Crystallography, A. Mickiewicz University, Polish Academy of Sciences, Grunwaldzka 6, 60-780 Poznan, Poland.
    Grubb, A.
    Department of Clinical Chemistry, University Hospital, S-22185 Lund, Sweden.
    Prevention of domain swapping inhibits dimerization and amyloid fibril formation of cystatin C. Use of engineered disulfide bridges, antibodies, and carboxymethylpapain to stabilize the monomeric form of cystatin C2004In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, no 23, p. 24236-24245Article in journal (Refereed)
    Abstract [en]

    Amyloidogenic proteins like cystatin C and prion proteins have been shown to form dimers by exchange of subdomains of the monomeric proteins. This process, called "three-dimensional domain swapping," has also been suggested to play a part in the generation of amyloid fibrils. One variant of cystatin C, L68Q cystatin C, is highly amyloidogenic, and persons carrying the corresponding gene suffer from massive cerebral amyloidosis leading to brain hemorrhage and death in early adult life. The present work describes the production of two variants of wild type and L68Q cystatin C with disulfide bridges at positions selected to inhibit domain swapping without affecting the biological function of the four cystatin C variants as cysteine protease inhibitors. The capacity of the four variant proteins to form dimers was tested and compared with that of wild type and L68Q cystatin C. In contrast to the latter two proteins, all four protein variants stabilized by disulfide bridges were resistant toward the formation of dimers. The capacity of the two stabilized variants of wild type cystatin C to form amyloid fibrils was investigated and found to be reduced by 80% compared with that of wild type cystatin C. In an effort to investigate whether exogenous agents could also suppress the formation of dimers of wild type and L68Q cystatin C, a monoclonal antibody or carboxymethylpapain, an inactivated form of a cysteine protease, was added to systems inducing dimerization of wild type and L68Q cystatin C. It was observed that catalytic amounts of both the monoclonal antibody and carboxymethylpapain could suppress dimerization.

  • 31. Nilsson, Maria
    et al.
    Wang, Xin
    Rodziewicz-Motowidlo, Sylwia
    Janowski, Robert
    Lindström, Veronica
    Önnerfjord, Patrik
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Grzonka, Zbigniew
    Jaskolski, Mariusz
    Grubb, Anders
    Prevention of domain swapping inhibits dimerization and amyloid fibril formation of cystatin C2004In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, p. 24236-24245Article in journal (Refereed)
  • 32.
    Nilsson, Peter
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics .
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Ahlgren, Fredrik
    Division of Cell Biology Linköpings universitet.
    Herland, Anna
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics .
    Schnell, Edrun A
    The Norwegian University of Science and Technology.
    Lindgren, Mikael
    The Norwegian University of Science and Technology.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Inganäs, Olle
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics .
    Conjugated Polyelectrolytes - Conformation - Sensitive Optical Probes for staining and Characterization of Amyloid Deposits2006In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 7, p. 1096-1104Article in journal (Refereed)
    Abstract [en]

      

  • 33.
    Nilsson, Peter
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Åslund, Andreas
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry.
    Berg, Ina
    Nyström, Sofie
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Konradsson, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry.
    Herland, Anna
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics.
    Inganäs, Olle
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics.
    Stabo-Eeg, Frantz
    Lindgren, Mikael
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Lannfelt, Lars
    Nilsson, Lars N G
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Imaging distinct conformational states of amyloid-β fibrils in Alzheimer's disease using novel luminescent probes2007In: ACS Chemical Biology, ISSN 1554-8929, Vol. 2, no 8, p. 553-560Article in journal (Refereed)
    Abstract [en]

    Using luminescent conjugated polyelectrolyte probes (LCPs), we demonstrate the possibility to distinguish amyloid-β 1-42 peptide (Aβ1-42) fibril conformations, by analyzing in vitro generated amyloid fibrils of Aβ1-42 formed under quiescent and agitated conditions. LCPs were then shown to resolve such conformational heterogeneity of amyloid deposits in vivo. A diversity of amyloid deposits depending upon morphology and anatomic location was illustrated with LCPs in frozen ex vivo brain sections from a transgenic mouse model (tg-APPswe) of Alzheimer's disease. Comparative LCP fluorescence showed that compact-core plaques of amyloid β precursor protein transgenic mice were composed of rigid dense amyloid. A more abundant form of amyloid plaque displayed morphology of a compact center with a protruding diffuse exterior. Surprisingly, the compact center of these plaques showed disordered conformations of the fibrils, and the exterior was composed of rigid amyloid protruding from the disordered center. This type of plaque appears to grow from more loosely assembled regions toward solidified amyloid tentacles. This work demonstrates how application of LCPs can prove helpful to monitor aggregate structure of in vivo formed amyloid deposits such as architecture, maturity, and origin.

  • 34.
    Nyström, Sofia N.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T.
    Uppsala University, Sweden.
    AA-Amyloid is cleared by endogenous immunological mechanisms2012In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 19, no 3, p. 138-145Article in journal (Refereed)
    Abstract [en]

    Reactive amyloidosis is a complication to longstanding inflammatory diseases.Protein amyloid A (AA), an N-terminal fragment of the acute phase protein serumamyloid A, undergoes conformational changes and is deposited as amyloid in tissue.AA-amyloidosis is reversible and reduction of amyloid mass has been reported as theinflammation ceases. Not much is known about the endogenous factors thatcontribute to amyloid resolution. Herein, we describe the dynamics of amyloiddegradation in experimental murine AA-amyloidosis and show that amyloiddegradation depends on macrophages and antibody formation. AA-amyloidosis wasinduced in mice and resolution of amyloid was monitored over time by histologicaltechniques. Internalized amyloid was present in macrophages that appeared at siteof deposition. At 9 months, when virtually all amyloid was cleared, amyloidosis wasre-induced in one group of animals by a single silver nitrate injection. This causedeposition of excessive amounts of amyloid, and indicate that even thoughundetectable the amyloid reseed in the body and can there act as amyloid enhancingfactor. Antibodies directed against protein AA were detected in animals duringamyloid clearance by ELISA-technique. Passive immunization with an amyloidspecific monoclonal antibody, produced by a B-cell clone recovered from an animalwith advanced AA-amyloidosis, diminish amyloid deposits in murine AA-amyloidosis.Immunoglobulins co-localize with amyloid deposits and can contribute to amyloiddegradation by Fc-receptor mediated phagocytosis.

  • 35.
    Nyström, Sofia N.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Cardiac Amyloid in Experimental AA Amyloidosis is Associated with IncreasedAutophagic ActivityManuscript (preprint) (Other academic)
    Abstract [en]

    Cardiac involvement in reactive amyloidosis is a severe complication that leads to reducedsurvival. We induced reactive amyloidosis in mice by induction of chronic inflammation andfound that cardiac involvement develops later than spleen and liver deposits. TEM studiesrevealed intracellular amyloid deposits, but endogenous production of SAA1, SAA2 or SAA3by the cardiomyocytes was not supported by mRNA analysis. Therefore, the intracellulardeposits of protein AA must derive from SAA produced at another location. Autophagosomeswere present in close association with intracellular amyloid and the autophagy marker LC3was increased 20 times in cardiac tissue with moderate amounts of amyloid. Increase in LC3was not paralleled by an increase in LAMP-2. The ER-stress marker Bip was unchanged ininflamed heart tissue and in amyloid-containing heart. Even though procaspase-12 increasedin heart after silver nitrate injections and in heart with AA-amyloid, no active caspase-12could be detected. We suggest that autophagosomes are involved in amyloid clearance, buttheir accumulation indicate that the formation of autophagolysosomes is hampered.

  • 36.
    Paulsson, Johan
    et al.
    Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
    Andersson, A.
    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Westermark, P.
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Westermark, Gunilla
    Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
    Intracellular amyloid-like deposits contain unprocessed pro-islet amyloid polypeptide (proIAPP) in beta cells of transgenic mice overexpressing the gene for human IAPP and transplanted human islets2006In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 49, no 6, p. 1237-1246Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Islet amyloid is a frequent finding in the islets of Langerhans of individuals with type 2 diabetes. The main amyloid constituent is the beta cell-derived polypeptide hormone islet amyloid polypeptide (IAPP). In general, amyloid refers to an extracellular deposit of a congophilic material, but intracellular amyloid is seen in some beta cells of transgenic mice expressing the gene for human IAPP and in human islets transplanted into nude mice. The aim of this study was to immunohistochemically characterise the intracellular amyloid. Methods: Antisera against the N- and C-terminal processing sites of proIAPP (which were therefore specific for proIAPP), the C-terminal flanking peptide and mature IAPP were used for immunoelectron microscopy. Results: Fibrillar aggregates were seen in the halo region of the secretory granules in some beta cells in human IAPP transgenic mice. These aggregates were labelled with proIAPP-specific antisera. Also, proIAPP reactivity was more widespread in the intracellular amyloid-like aggregates in beta cells of transgenic mice than in human islet transplants, in which the intracellular amyloid-like deposits were larger, but the proIAPP labelling was restricted to small spots within the amyloid deposits. Conclusions/ interpretation: We suggest that proIAPP forms the first amyloid fibrils and that this can occur already in the secretory granules of the beta cells. The proIAPP-derived fibrils can act as seed for further amyloid formation, now made up by IAPP. The observed difference between human islet transplants and human IAPP transgenic animals may reflect differences in stages of amyloid development. © Springer-Verlag 2006.

  • 37.
    Paulsson, Johan F
    et al.
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
    Schultz, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    João Saraiva, Maria
    Amyloid Unit, Institute for Molecular and Cell Biology, Porto, Portugal.
    Kapurniotu, Aphrodite
    Physiological-Chemical Institute, University of Tübingen, Tübingen, Germany.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    There is a role for proIAPP in islet amyloid fibrillogenesis2008Manuscript (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.

  • 38.
    Paulsson, Johan F
    et al.
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
    Schultz, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kohler, Martin
    The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institute, 17176 Stockholm, Sweden.
    Leibiger, Ingo
    The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institute, 17176 Stockholm, Sweden.
    Berggren, Per-Olof
    The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institute, 17176 Stockholm, Sweden.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Real-Time Monitoring of Apoptosis by Caspase-3-Like Protease Induced FRET Reduction Triggered by Amyloid Aggregation2008In: Experimental Diabetes Research, ISSN 1687-5214, E-ISSN 1687-5303, Vol. 2008, no 865850Article in journal (Refereed)
    Abstract [en]

    Amyloid formation is cytotoxic and can activate the caspase cascade. Here, we monitor caspase-3-like activity as reduction of fluorescence resonance energy transfer (FRET) using the contstruct pFRET2-DEVD containing enhanced cyan fluorescent protin (EYFP) linked by the caspase-3 specific cleavage site residues DEVD. Beta-TC-6 cells were transfected, and the fluoorescence was measured at 440 nm excitation and 535 nm (EYFP) and 480 nm (ECFP) emission wavelength. Cells were incubated with recombinant pro lset Amyloid Polypeptide (rec prolAPP) or the processing metabolites of prolAPP; the N-terminal flanking peptide withIAPP (recN+IAPP); IAPP with the C-terminal flanking peptied (recIAPP+C) and lslet Amyloid Polypeptide (recIAPP). Peptides were added in solubilized from (50 mu M) or as performed amyloid-like fibrils, or as a combination of these. FRET was measured and incubation with a mixture of solubilized peptide and performed fibrils resulted in loss of FRET and apoptosis was determined to occurein cells incubated with recproIAPP (49%), recN+IAPP (46%), recIAPP (72%) and recIAPP+C (59%). These results show that proIAPP and the processing intermediates reside the same cell toxic capacity as IAPP, and they can all have a central role in the reduction of beta-cell number in type 2 diabetes.

  • 39.
    Paulsson, Johan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Aberrant processing of human proislet amyloid polypeptide results in increased amyloid formation2005In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 54, no 7, p. 2117-2125Article in journal (Refereed)
    Abstract [en]

    The amyloid present in the islets of Langerhans in type 2 diabetes is polymerized islet amyloid polypeptide (IAPP). The precursor protein proIAPP is posttranslationally modified, a process involving the removal of NH2- and COOH-terminal flanking peptides. This step is performed by the prohormone convertases PC2 and PC1/3. PC2 processes proIAPP preferably at the NH 2-terminal processing site, and PC1/3 processes proIAPP exclusively at the COOH-terminal site. Little is known regarding the exact circumstances leading to islet amyloid formation. In this study, we have examined the possible significance of aberrant processing of proIAPP on amyloid formation in several in vitro cellular systems. In our studies, human (h)-proIAPP was transfected into β-TC-6 cells expressing both prohormone convertases and in which proIAPP is processed into IAPP. Additionally, h-proIAPP was transfected into three different pituitary-derived cell lines with different prohormone convertase profiles: AtT-20 cells (deficient in PC2), GH3 cells (deficient in PC1/3), and GH4C1 cells (deficient in both convertases). We followed the processing of h-proIAPP with antibodies specific for the respective cleavage sites and stained the cells with Congo red to verify the accumulation of amyloid. Incomplete processing of h-proIAPP that occurs in AtT-20 and GH4C1 cells resulted in the formation of intracellular amyloid. No amyloid developed in β-TC-6 and GH3 cells lines with full processing of proIAPP. An intracellular increase in proIAPP and/or its metabolic products may thus promote intracellular amyloid formation, thereby causing cell death. When extracellularly exposed, this amyloid might act as template for continuing amyloid formation from processed IAPP released from the surrounding β-cells. © 2005 by the American Diabetes Association.

  • 40.
    Paulsson, Johan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Differences in distribution of insulin and IAPP on the cellular level2001In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 8, p. 132-132Conference paper (Other academic)
  • 41.
    Peng, S.
    et al.
    Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Naslund, J.
    Näslund, J., Department of Clinical Neuroscience, Occupational Therapy, and Elderly Care Research (NEUROTEC), Section for Geriatrics, Karolinska Institute, Huddinge, Sweden.
    Häggqvist, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology .
    Glennert, J.
    Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Westermark, P.
    Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
    A computer-based training system for breast fine needle aspiration cytology2002In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 196, no 1, p. 113-121Article in journal (Refereed)
    Abstract [en]

    Fine-needle aspiration (FNA) cytology is a rapid and inexpensive technique used extensively in the diagnosis of breast disease. To remove diagnostic subjectivity, a diagnostic decision support system (DDSS) called CytoInform© has been developed, based on a Bayesian belief network (BBN) for the diagnosis of breast FNAs. In addition to acting as a DDSS, the system implements a computer-based training (CBT) system, providing a novel approach to breast cytology training. The system guides the trainee cytopathologist through the diagnostic process, allowing the user to grade each diagnostic feature using a set of on-screen reference images as visual clues. The trainee positions a slider on a spectrum relative to these images, reflecting the similarity between the reference image and the microscope image. From this, an evidence vector is generated, allowing the current diagnostic probability to be updated by the BBN. As the trainee assesses each clue, the evidence entered is compared with that of the expert through the use of a defined teaching file. This file records the relative severity of each clue and a tolerance band within which the trainee must position the slider. When all clues in the teaching case have been completed, the system informs the user of inaccuracies and offers the ability to reassess problematic features. In trials with two pathologists of different experience and a series of ten cases, the system provided an effective tool in conveying diagnostic evidence and protocols to trainees. This is evident from the fact that each pathologist only misinterpreted one case and a total of 86%/88% (experienced/inexperienced) of all clues assessed were interpreted correctly. Significantly, in all cases that produced the correct final diagnostic probability, the route taken to that solution was consistent with the expert's solution. Copyright © 2001 John Wiley & Sons, Ltd.

  • 42. Peng, Siwei
    et al.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Näslund, Jan
    Häggqvist, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Glennert, Johanna
    Westermark, Per
    Medin and medin-amyloid in ageing inflamed and non-inflamed temporal arteries2002In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 196, p. 91-96Article in journal (Refereed)
  • 43. Peng, SW
    et al.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Sletten, K
    Glennert, J
    Westermark, P
    Distribution of medin-amyloid in aging and in association with arterial diseases2001In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 8, p. 122-123Conference paper (Other academic)
  • 44.
    Sauma, Lilian
    et al.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Franck, Niclas
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Paulsson, Johan F
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kjølhede, Preben
    Linköping University, Department of Molecular and Clinical Medicine. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Söderström, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik H.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes2007In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 50, no 1, p. 195-201Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The amount of visceral fat mass strongly relates to insulin resistance in humans. The transcription factor peroxisome proliferator activated receptor gamma (PPARG) is abundant in adipocytes and regulates genes of importance for insulin sensitivity. Our objective was to study PPARG activity in human visceral and subcutaneous adipocytes and to compare this with the most common model for human disease, the mouse.

    MATERIALS AND METHODS: We transfected primary human adipocytes with a plasmid encoding firefly luciferase controlled by PPARG response element (PPRE) from the acyl-CoA-oxidase gene and measured PPRE activity by emission of light. RESULTS: We found that PPRE activity was 6.6-fold higher (median) in adipocytes from subcutaneous than from omental fat from the same subjects (n = 23). The activity was also 6.2-fold higher in subcutaneous than in intra-abdominal fat cells when we used a PPARG ligand-binding domain-GAL4 fusion protein as reporter, demonstrating that the difference in PPRE activity was due to different levels of activity of the PPARG receptor in the two fat depots. Stimulation with 5 micromol/l rosiglitazone did not induce a PPRE activity in visceral adipocytes that was as high as basal levels in subcutaneous adipocytes. Interestingly, in mice of two different strains the PPRE activity was similar in visceral and subcutaneous fat cells.

    CONCLUSIONS/INTERPRETATION: We found considerably lower PPARG activity in visceral than in subcutaneous primary human adipocytes. Further studies of the molecular mechanisms behind this difference could lead to development of drugs that target the adverse effects of visceral obesity.

  • 45.
    Schultz, Sebastian
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Gu, Xiaohong
    Department of Medical Cell Biology, Uppsala University, SE-­‐75123, Uppsala, Sweden.
    Rusten, Tor Erik
    Centre for Cancer Biomedicine, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, N-­‐0317, Oslo, Norway.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    HIAPP and hproIAPP triggers elective autophagy and inhibit the neuro-­protective effect of autophagy2010Manuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: Amyloid formation is associated with cell death and islet amyloid is thought to participate in the 50-60% β-cell reduction detected in patients with type 2 diabetes. Islet amyloid polypeptide (IAPP) is the main amyloid protein in the islets of Langerhans. Initial IAPP-amyloid formation is intracellular and part of this amyloid constitutes of proIAPP.

    Material & methods: We have established a new model in Drosophila melanogaster where expression of hproIAPP and IAPP results in the formation of amyloid. With this model, we have investigated the effect of protein aggregation on pathways such as ER-stress, unfolded protein response (UPR), apoptosis and autophagy. Important steps in the different pathways were manipulated by RNAi-technique or over- expression of endogenous Drosophila proteins.

    Results: Expression of hproIAPP and hIAPP driven to the pdf-neurons led to cell death, but this was without activation of ER-stress, UPR or apoptosis. Aggregated hproIAPP and IAPP, labeled with antibodies against ubiquitin and p62 were accumulated intracellular, a finding that points to an involvement of autophagy. HproIAPP and hIAPP were shown to exert their toxic activity by an intracellular mechanism in contrary to Aβ42 and Aβ42 E22G that exhibit an extracellular toxic activity.

    Conclusion: Studies on toxicity suggest that hproIAPP and hIAPP aggregates can occupy the autophagy pathway and prevent maintenance of basal cellular homeostasis. Comparison of proIAPP/IAPP and Aβ42 toxicity shows that amyloid proteins of separate origin can exhibit different toxicity.

  • 46.
    Schultz, Sebastian
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Fly model of type 2 diabetes: processing of proIAPP makes a difference2010In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 17, no S1, p. 44-45Article in journal (Other academic)
    Abstract [en]

    Patients  with type 2 diabetes  have a marked  reducedbeta cell mass and fail to produce  sufficient amounts of insulin required  for regulation  of glucose home- ostasis. Recent research supports that intracellular aggregation of islet amyloid polypeptide  (IAPP) leads to cell death and therefore makes IAPP aggregation a plausible cause for the beta cell reduction. Little is known about the mechanisms that precede amyloid formation  or which cellular pathways are involved in this process.  To  gain better  understanding we haveestablished  a Drosophila melanogaster model,  where GAL4 drives expression  of UAS-targeted transgenes in a cell or tissue specific pattern. The  fruit fly offers a unique  option  to manipulate any cellular  pathway with  different   genetic   tools.   The   knowledge   that*70%  of all Drosophila  melanogaster genes  have anorthologue in humans  stress  the  potential  for path- ways found in D. melanogaster to be of importance in humans  as well. Transgenic flies expressing  human proIAPP  (the precursor of IAPP)  and IAPP and the non-amyloidogenic mouse IAPP (mIAPP) have been generated.  Expression    of  proIAPP    in   the   brain reduced the lifespan of the fly whereas neither  IAPP nor mIAPP expression influenced survival. Immu- nolabelling  with  an  antibody  raised  against  human IAPP   and   that   cross-reacts    with   murine    IAPP labelled neurons  in all three strains, whereas a concomitant loss of cell nuclei only appeared  during proIAPP and IAPP expression. Furthermore, we detected  an early potentiated activation of the autophagy  pathway  in  proIAPP   flies. Interestingly, even  though  IAPP  expression  was not  related  to  a shorter  lifespan, both IAPP and proIAPP  expression in the  central  nervous  system  led  to  amyloid deposition  in the fat body of the head as shown with Congo  red  and  pFTAA,   a  newly  synthesised luminescent conjugated polymer. Our results de- monstrate that  D. melanogaster has a great  potential as a model  for studies  of proIAPP  and  IAPP expression with subsequent amyloid formation  and connected cellular  response  mechanisms. The  find- ing that proIAPP  aggregation  seems to exert a more toxic  impact  at  a  cellular  level is in  line  with  ourresults from mammalian cell lines.

  • 47.
    Schultz, Sebastian
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Westermark , Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Drosophila melanogaster - a model system for protein aggregation2009In: The 12th European Drosophila Neurobiology Conference 6-10 September 2008 Wuerzburg, Germany: in: Journal of Neurogenetics, Volume 23 Supplement 1 2009, 2009, Vol. 23, p. S12-S12Conference paper (Refereed)
  • 48. Solomon, A
    et al.
    Murphy, CL
    Weaver, K
    Weiss, DT
    Hrncic, R
    Eulitz, M
    Donnell, RL
    Sletten, K
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Westermark, P
    Calcifying epithelial odontogenic (Pindborg) tumor-associated amyloid consists of a novel human protein2003In: Journal of Laboratory and Clinical Medicine, ISSN 1931-5244, E-ISSN 1878-1810, Vol. 142, no 5, p. 348-355Article in journal (Refereed)
    Abstract [en]

    Calcifying epithelial odontogenic tumors (CEOTs), also known as Pindborg tumors, are characterized by the presence of squamous-cell proliferation, calcification, and, notably, amyloid deposits. On the basis of immunohistochemical analyses, the amyloidogenic component had heretofore been deemed to consist of cytokeratin-related or other molecules, however, its chemical composition had never been elucidated. We have used our microanalytic techniques to characterize the protein nature of CEOT-associated amyloid isolated from specimens obtained from 3 patients. As evidenced by the results of amino-acid sequencing and mass spectrometry, the fibrils were found to be composed of a polypeptide of approximately 46 mer. This component was identical in sequence to the N-terminal portion of a hypothetical 153-residue protein encoded by the FLJ20513 gene cloned from the human KATO III cell line. That the amyloid protein was derived from this larger molecule was demonstrated by reverse transcription-polymerase chain reaction amplification of tumor-cell RNA where a full-length FLJ20513 transcript was found. Furthermore, immunohistochemical analyses revealed that the amyloid within the CEOTs immunostained with antibodies prepared against a synthetic FLJ20513-related dodecapeptide. Out studies provide unequivocal evidence that CEOT-associated amyloid consists of a unique and previously undescribed protein that we provisionally designate APin.

  • 49.
    Solomon, A.
    et al.
    Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, United States, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37920, United States.
    Richey, T.
    Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, United States.
    Murphy, C.L.
    Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, United States.
    Weiss, D.T.
    Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, United States.
    Wall, J.S.
    Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, United States.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Westermark, P.
    Department of Genetics and Pathology, Uppsala University, SE-75185 Uppsala, Sweden.
    Amyloidogenic potential of foie gras2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 26, p. 10998-11001Article in journal (Refereed)
    Abstract [en]

    The human cerebral and systemic amyloidoses and prion-associated spongiform encephalopathies are acquired or inherited protein folding disorders in which normally soluble proteins or peptides are converted into fibrillar aggregates. This is a nucleation-dependent process that can be initiated or accelerated by fibril seeds formed from homologous or heterologous amyloidogenic precursors that serve as an amyloid enhancing factor (AEF) and has pathogenic significance in that disease may be transmitted by oral ingestion or parenteral administration of these conformationally altered components. Except for infected brain tissue, specific dietary sources of AEF have not been identified. Here we report that commercially available duck- or goose-derived foie gras contains birefringent congophilic fibrillar material composed of serum amyloid A-related protein that acted as a potent AEF in a transgenic murine model of secondary (amyloid A protein) amyloidosis. When such mice were injected with or fed amyloid extracted from foie gras, the animals developed extensive systemic pathological deposits. These experimental data provide evidence that an amyloid-containing food product hastened the development of amyloid protein A amyloidosis in a susceptible population. On this basis, we posit that this and perhaps other forms of amyloidosis may be transmissible, akin to the infectious nature of prion-related illnesses. © 2007 by The National Academy of Sciences of the USA.

  • 50.
    Sponarová, Jana
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    AA-amyloidosis can be transferred by peripheral blood monocytes2008In: PloS one, ISSN 1932-6203, Vol. 3, no 10, p. e3308-Article in journal (Refereed)
    Abstract [en]

    Spongiform encephalopathies have been reported to be transmitted by blood transfusion even prior to the clinical onset. Experimental AA-amyloidosis shows similarities with prion disease and amyloid-containing organ-extracts can prime a recipient for the disease. In this systemic form of amyloidosis N-terminal fragments of the acute-phase reactant apolipoprotein serum amyloid A are the main amyloid protein. Initial amyloid deposits appear in the perifollicular region of the spleen, followed by deposits in the liver. We used the established murine model and induced AA-amyloidosis in NMRI mice by intravenous injections of purified amyloid fibrils ('amyloid enhancing factor') combined with inflammatory challenge (silver nitrate subcutaneously). Blood plasma and peripheral blood monocytes were isolated, sonicated and re-injected into new recipients followed by an inflammatory challenge during a three week period. When the animals were sacrificed presence of amyloid was analyzed in spleen sections after Congo red staining. Our result shows that some of the peripheral blood monocytes, isolated from animals with detectable amyloid, contained amyloid-seed that primed for AA-amyloid. The seeding material seems to have been phagocytosed by the cells since the AA-precursor (SAA1) was found not be expressed by the monocytes. Plasma recovered from mice with AA amyloidosis lacked seeding capacity. Amyloid enhancing activity can reside in monocytes recovered from mice with AA-amyloidosis and in a prion-like way trigger amyloid formation in conjunction with an inflammatory disorder. Human AA-amyloidosis resembles the murine form and every individual is expected to be exposed to conditions that initiate production of the acute-phase reactant. The monocyte-transfer mechanism should be eligible for the human disease and we point out blood transfusion as a putative route for transfer of amyloidosis.

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