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  • 1.
    Anan, Intissar
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Bång, Joakim
    Umea Univ, Dept Surg & Perioperat Sci Orthopaed, Umea, Sweden.
    Lundgren, Hans-Erik
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Wixner, Jonas
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    A case report of osteoarthritis associated with hereditary transthyretin amyloidosis ATTRV30M2019In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, no Suppl. 1, p. 29-30Article in journal (Refereed)
  • 2.
    Andersson, Arne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bohman, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Borg, L. A. Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Paulsson, Johan F.
    Schultz, Sebastian W.
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Amyloid deposition in transplanted human pancreatic islets: a conceivable cause of their long-term failure2008In: Experimental diabetes research, ISSN 1687-5214, Vol. 2008, p. 562985-Article, review/survey (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.

  • 3. Andersson, Marlene
    et al.
    Chen, Gefei
    Otikovs, Martins
    Landreh, Michael
    Nordling, Kerstin
    Kronqvist, Nina
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Jornvall, Hans
    Knight, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Ridderstrale, Yvonne
    Holm, Lena
    Meng, Qing
    Jaudzems, Kristaps
    Chesler, Mitchell
    Johansson, Jan
    Rising, Anna
    Carbonic Anhydrase Generates CO2 and H+ That Drive Spider Silk Formation Via Opposite Effects on the Terminal Domains2014In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 12, no 8, p. e1001921-Article in journal (Refereed)
    Abstract [en]

    Spider silk fibers are produced from soluble proteins (spidroins) under ambient conditions in a complex but poorly understood process. Spidroins are highly repetitive in sequence but capped by nonrepetitive N- and C-terminal domains (NT and CT) that are suggested to regulate fiber conversion in similar manners. By using ion selective microelectrodes we found that the pH gradient in the silk gland is much broader than previously known. Surprisingly, the terminal domains respond in opposite ways when pH is decreased from 7 to 5: Urea denaturation and temperature stability assays show that NT dimers get significantly stabilized and then lock the spidroins into multimers, whereas CT on the other hand is destabilized and unfolds into ThT-positive beta-sheet amyloid fibrils, which can trigger fiber formation. There is a high carbon dioxide pressure (pCO(2)) in distal parts of the gland, and a CO2 analogue interacts with buried regions in CT as determined by nuclear magnetic resonance (NMR) spectroscopy. Activity staining of histological sections and inhibition experiments reveal that the pH gradient is created by carbonic anhydrase. Carbonic anhydrase activity emerges in the same region of the gland as the opposite effects on NT and CT stability occur. These synchronous events suggest a novel CO2 and proton-dependent lock and trigger mechanism of spider silk formation.

  • 4.
    Antoni, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Axelsson, Jan
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lindsjö, Lars
    Kero, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Granstam, Sven-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Rosengren, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Vedin, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    In Vivo Visualization of Amyloid Deposits in the Heart with 11C-PIB and PET2013In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, no 2, p. 213-220Article in journal (Refereed)
    Abstract [en]

    Cardiac amyloidosis is a differential diagnosis in heart failure and is associated with high mortality. There is currently no noninvasive imaging test available for specific diagnosis. N-[methyl-11C]2-(4′-methylamino-phenyl)-6-hydroxybenzothiazole (11C-PIB) PET is used in the evaluation of brain amyloidosis. We evaluated the potential use of 11C-PIB PET in systemic amyloidosis affecting the heart.

    Methods:

    Patients (n = 10) diagnosed with systemic amyloidosis—including heart involvement of either monoclonal immunoglobulin light-chain (AL) or transthyretin (ATTR) type—and healthy volunteers (n = 5) were investigated with PET/CT using 11C-PIB to study cardiac amyloid deposits and with 11C-acetate to measure myocardial blood flow to study the impact of global and regional perfusion on PIB retention.

    Results:

    Myocardial 11C-PIB uptake was visually evident in all patients 15–25 min after injection and was not seen in any volunteer. A significant difference in 11C-PIB retention in the heart between patients and healthy controls was found. The data indicate that myocardial amyloid deposits in patients diagnosed with systemic amyloidosis could be visualized with 11C-PIB. No correlation between 11C-PIB retention index and myocardial blood flow as measured with 11C-acetate was found on the global level, whereas a positive correlation on the segmental level was seen in a single patient.

    Conclusion:

    11C-PIB and PET could be a method to study systemic amyloidosis of type AL and ATTR affecting the heart and should be investigated further both as a diagnostic tool and as a noninvasive method for treatment follow-up.

  • 5.
    Arvidsson, Sandra
    et al.
    Umea Univ, Dept Clin Physiol, Ctr Heart, Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Pilebro, Bjorn
    Umea Univ, Dept Cardiol, Ctr Heart, Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lindqvist, Per
    Umea Univ, Dept Clin Physiol, Ctr Heart, Umea, Sweden.;Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden..
    Suhr, Ole B.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, article id e0143456Article in journal (Refereed)
    Abstract [en]

    Purpose Transthyretin V30M (ATTR V30M) amyloidosis is a phenotypically diverse disease with symptoms ranging from predominant neuropathy to exclusive cardiac manifestations. The aims of this study were to determine the dispersion of the two types of fibrils found in Swedish ATTR V30M patients - Type A consisting of a mixture of truncated and full length ATTR fibrils and type B fibrils consisting of full length fibrils, and to estimate the severity of cardiac dysfunction in relation to fibril composition and sex. Material and Methods Echocardiographic data were analysed in 107 Swedish ATTR V30M patients with their fibril composition determined as either type A or type B. Measurements of left ventricular (LV) dimensions and evaluation of systolic and diastolic function including speckle tracking derived strain were performed. Patients were grouped according to fibril type and sex. Multivariate linear regression was utilised to determine factors of significant impact on LV thickness. Results There was no significant difference in proportions of the two types of fibrils between men and women. In patients with type A fibrils, women had significantly lower median septal (p = 0.007) and posterior wall thicknesses (p = 0.010), lower median LV mass indexed to height (p = 0.008), and higher septal strain (p = 0.037), as compared to males. These differences were not apparent in patients with type B fibrils. Multiple linear regression analysis revealed that fibril type, sex and age all had significant impact on LV septal thickness. Conclusion This study demonstrates a clear difference between sexes in the severity of amyloid heart disease in ATTR V30M amyloidosis patients. Even though type A fibrils were associated with more advanced amyloid heart disease compared to type B, women with type A fibrils generally developed less cardiac infiltration than men. The differences may explain the better outcome for liver transplanted late-onset female patients compared to males.

  • 6.
    Bellotti, Vittorio
    et al.
    UCL, Div Med, Ctr Amyloidosis & Acute Phase Prot, Wolfson Drug Discovery Unit, London, England;Univ Pavia, Inst Biochem, Dept Mol Med, Pavia, Italy.
    Merlini, Giampaolo
    Univ Pavia, Fdn IRCCS Policlin San Matteo, Amyloidosis Res & Treatment Ctr, Biotechnol Res Labs,Dept Mol Med, Pavia, Italy.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Biographical item "Robert Kisilevsky, Md, Phd, 1937-2019 In Memoriam", in Amyloid: The Journal of Protein Folding Disorders Volume 26, 2019, Issue 4, p 179.2019Other (Other (popular science, discussion, etc.))
  • 7.
    Benson, Merrill D.
    et al.
    Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN USA.
    Buxbaum, Joel N.
    Scripps Res Inst, Dept Mol Med, La Jolla, CA USA.
    Eisenberg, David S.
    Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA USA.
    Merlini, Giampaolo
    Univ Pavia, Amyloid Res & Treatment Ctr, Pavia, Italy; IRCCS Policlin San Matteo, Pavia, Italy.
    Saraiva, Maria J. M.
    Univ Porto, Inst Mol & Cellular Biol, Amyloid Unit, Porto, Portugal.
    Sekijima, Yoshiki
    Shinshu Univ, Sch Med, Dept Med Neurol & Rheumatol, Matsumoto, Nagano, Japan.
    Sipe, Jean D.
    Boston Univ, Sch Med, Dept Biochem, Boston, MA USA.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee2018In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 25, no 4, p. 215-219Article in journal (Refereed)
    Abstract [en]

    The nomenclature committee of the International Society of Amyloidosis (ISA) meets every second year to discuss and formulate recommendations. The conclusions from the discussion at the XVI International Symposium on Amyloidosis in Kumamoto, Japan, 25–29 March 2018 and afterwards are summarized in this Nomenclature Article. From having recommended the use of the designation “amyloid fibril” for in vivo material only, ISA’s nomenclature committee now accepts its use more broadly following the international scientific literature. However, it is important always to stress the origin of the β-fibrils in order to avoid misunderstanding. Given the more broad use of the word “amyloid” several classes of amyloid fibrils may be distinguished. For the medical in vivo situation, and to be included in the amyloid nomenclature list, “amyloid” still means mainly extracellular tissue deposits of protein fibrils, recognized by specific properties, such as green-yellow birefringence after staining with Congo red. It should also be underlined that in vivo amyloid fibrils, in addition to the main protein contain associated compounds, particularly serum amyloid P-component (SAP) and proteoglycans, mainly heparan sulfate proteoglycan. With this definition there are presently 36 human amyloid proteins of which 14 appear only associated with systemic amyloidosis and 19 as localized forms. Three proteins can occur both as localized and systemic amyloidosis. Strictly intracellular aggregates are not included in this list.

  • 8.
    Bergström, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Engström, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Yamashita, Taro
    Ando, Yukio
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Surface exposed epitopes and structural heterogeneity of in vivo formed transthyretin amyloid fibrils2006In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 348, no 2, p. 532-539Article in journal (Refereed)
    Abstract [en]

    We have investigated the structure of in vivo formed transthyretin (TTR) amyloid deposits by using antisera raised against short linear sequences of the TTR molecule. In immunohistochemistry, antisera anti-TTR41-50 and anti-TTR115-124-a reacted specifically with both wildtype ATTR and ATTR V30M material, whereas only anti-TTR41-50 recognized ATTR Y114C material. Similar results were obtained by ELISA analysis of ATTR V30M and ATTR Y114C vitreous amyloid, where the anti-TTR115-124-a antiserum failed to react with ATTR Y114C material. Moreover, neither of the antisera recognized natively structured TTR present in pancreatic alpha cells. Our results strongly indicate that the TTR molecule undergoes structural changes during fibrillogenesis in vivo. The finding of a structural difference between wildtype ATTR and ATTR V30M material on one hand and ATTR Y114C material on the other suggests that the fibril formation pathway of these ATTR variants may differ in vivo.

  • 9.
    Bergström, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gustavsson, Åsa
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Sletten, Knut
    Murphy, Charles
    Weiss, Deborah
    Solomon, Alan
    Olofsson, Bert-Ove
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Amyloid deposits in transthyretin derived amyloidosis: Cleaved transthyretin is associated with distinct amyloid morphology2005In: The Internet Journal of Pathology, ISSN 1528-8307, Vol. 206, no 2, p. 224-232Article in journal (Refereed)
    Abstract [en]

    The pathological fibrillar deposits found in the heart and other organs of patients with senile systemic amyloidosis (SSA) and Swedish familial amyloidotic polyneuropathy (FAP) contain wild-type (wt) and a mutant form of transthyretin (TTR), respectively. Previously, it was reported that these two forms of amyloid have different molecular features and it was thus postulated that the mechanism responsible for TTR fibrillogenesis in SSA and FAP may differ. To document further the nature of the amyloid in these entities, detailed morphological, histochemical, immunological, and structural analyses of specimens obtained from 14 individuals with SSA and 11 Swedish FAP patients have been performed. Two distinct patterns of amyloid deposition (designated A and B) were evident. In pattern A, found in all SSA and five of 11 FAP cases, the amyloid had a homogeneous but patchy distribution within the sub-endocardium, sub-epicardium, and myocardium; exhibited weak congophilia and green birefringence; and was composed of tightly packed, short, unorientated fibrils. This material contained mainly approximately 79-residue C-terminal fragments of the amyloidogenic precursor protein. In pattern B, seen in the six other FAP patients, the amyloid appeared as thin streaks throughout the cardiac tissue; often surrounded individual muscle cells; was strongly congophilic and birefringent; had long fibrils arranged in parallel bundles, often penetrating into myocytes; and was composed of virtually intact TTR molecules. These findings provide substantive evidence for the morphological and structural heterogeneity of TTR fibrils and suggest that the two types of deposition may reflect fundamental differences in the pathogenesis of the TTR-associated amyloidoses.

  • 10.
    Bergström, Joakim
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Murphy, Charles L.
    Weiss, Deborah T.
    Solomon, Alan
    Sletten, Knut
    Hellman, Ulf
    Ludwiginstitutet för Cancerforskning.
    Westermark, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Two different types of amyloid deposits - apolipoprotein A-IV and transthyretin - in a patient with systemic amyloidosis2004In: Lab. Invest., Vol. 84, p. 981-988Article in journal (Refereed)
    Abstract [en]

    Certain forms of systemic amyloidosis have been associated with the pathologic deposition as fibrils of three different apolipoprotein-related proteins--apolipoprotein A-I, apolipoprotein A-II, and serum amyloid A. We have previously reported (Bergstrom et al, Biochem Biophys Res Commun 2001;285:903-908) that amyloid fibrils extracted from the heart of an elderly male with senile systemic amyloidosis contained, in addition to wild-type transthyretin-related molecules, an N-terminal fragment of yet a fourth apolipoprotein--apolipoprotein A-IV (apoA-IV). We now provide the results of our studies that have established the complete amino-acid sequence of this approximately 70-residue component and, additionally, have shown this protein to be the product of an unmutated apoA-IV gene. Notably, the apoA-IV and transthyretin fibrils were not codeposited but, rather, had anatomically distinct patterns of distribution within the heart and other organs, as evidenced immunohistochemically, by variation in the ultra structural morphology and by differences in the intensity of Congo red birefringence. These findings provide the first conclusive evidence that two separate forms of amyloid, each derived from a wild-type amyloidogenic precursor protein, were present in a patient with systemic amyloidosis.

  • 11. Bygum, Anette
    et al.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Brandrup, Flemming
    Ichthyosis prematurity syndrome: a well-defined congenital ichthyosis subtype2008In: The Journal of American Academy of Dermatology, ISSN 0190-9622, E-ISSN 1097-6787, Vol. 59, no 5 Suppl, p. S71-4Article in journal (Refereed)
    Abstract [en]

    Ichthyosis prematurity syndrome is a rare syndrome characterized by the clinical triad of premature birth, thick caseous desquamating epidermis, and neonatal asphyxia. We describe two siblings with ichthyosis prematurity syndrome. The index patient was born at gestational week 34. Immediately after birth he developed respiratory distress and needed intubation. Remarkable skin changes were noticed with universal red, edematous and desquamating, spongy skin giving an impression of excessive vernix caseosa. Marked regression of the edema and ichthyotic scaling was observed within a few weeks. The parents recalled that his elder sister had similar but milder skin changes and respiratory distress syndrome at birth. Ichthyosis prematurity syndrome was suggested and the diagnosis supported by electron microscopy of a skin biopsy specimen showing pathognomonic trilamellar membrane aggregations in the stratum corneum and stratum granulosum. Diagnosing this syndrome is important to reassure parents, obstetricians, and pediatricians about its benign course after complications in the perinatal period.

  • 12.
    Charkhkar, Ellahe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    The challenging histological diagnosis of transthyretin (ATTR) amyloidosis2017In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, no S1, p. 130-131Article in journal (Other academic)
  • 13.
    Enqvist, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mellqvist, Ulf-Henrik
    Department of Hematology, Sahlgrenska University Hospital, Gothenburg.
    Mölne, Johan
    Department of Pathology, Sahlgrenska University Hospital, Gothenburg.
    Sletten, Knut
    Biotechnology Center of Oslo, University of Oslo, Norway.
    Murphy, Charles
    Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, USA.
    Solomon, Alan
    Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, USA.
    Stevens, Fred J.
    Biosciences Division, Argonne National Laboratory, Argonne, USA.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    A father and his son with systemic AL amyloidosis2009In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 94, no 3, p. 437-439Article in journal (Refereed)
  • 14.
    Enqvist, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sletten, Knut
    Stevens, Fred J.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis2007In: PLoS ONE, ISSN 1932-6203, Vol. 2, no 10, p. e981-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Amyloid is insoluble aggregated proteins deposited in the extra cellular space. About 25 different proteins are known to form amyloid in vivo and are associated with severe diseases such as Alzheimeŕs disease, prion diseases and type-2 diabetes. Light chain (AL) -amyloidosis is unique among amyloid diseases in that the fibril protein, a monoclonal immunoglobulin light chain, varies between individuals and that no two AL-proteins with identical primary structures have been described to date. The variability in tissue distribution of amyloid deposits is considerably larger in systemic AL-amyloidosis than in any other form of amyloidosis. The reason for this variation is believed to be based on the differences in properties of the amyloidogenic immunoglobulin light chain. However, there is presently no known relationship between the structure of an AL-protein and tissue distribution. METHODOLOGY/PRINCIPAL FINDINGS: We compared the pattern of amyloid deposition in four individuals with amyloid protein derived from variable light chain gene O18-O8, the source of a high proportion of amyloidogenic light chains, and in whom all or most of the fibril protein had been determined by amino acid sequencing. In spite of great similarities between the structures of the proteins, there was a pronounced variability in deposition pattern. We also compared the tissue distribution in these four individuals with that of four other patients with AL-amyloid derived from the L2-L16 gene. Although the interindividual variations were pronounced, liver and kidney involvement was much more evident in the latter four. CONCLUSIONS/SIGNIFICANCE: We conclude that although the use of a specific gene influences the tissue distribution of amyloid, each light chain exhibits one or more determinants of organ-specificity, which originate from somatic mutations and post-translational modifications. Eventual identification of such determinants could lead to improved treatment of patients with AL amyloidosis.

  • 15.
    Enqvist, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sletten, Knut
    Biotechnology Centre of Oslo, University of Oslo, Norway.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fibril protein fragmentation pattern in systemic AL-amyloidosis2009In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 219, no 4, p. 473-480Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin light chain (AL)-amyloidosis was one of the first types of amyloidosis discovered and still little is known about its pathogenic mechanisms. One major obstacle is the very heterogeneous condition; in fact, every patient could be considered to have their own disease since symptoms and outcome vary enormously. The reason for this is not known but intrinsic factors of the immunoglobulin light chain (LC) and the fact that every LC is unique seem to be important. Post-translational modifications such as glycosylation and proteolysis are most certainly involved. By using western blotting, we studied in detail the proteolytic pattern in six patients with AL-amyloidosis of kappa type with the aid of three peptide antisera against two domains in the constant segment and one conserved domain in framework 3 of the variable region. Materials from one to five organs were analysed. The result clearly demonstrates that the fragmentation pattern was similar in amyloid of different organs in one patient but differed greatly between patients. Full-length, N-, and C-terminal fragments were detected with the three antisera. The results strongly support the hypothesis that proteolytic cleavage occurs after fibril formation.

  • 16.
    Galant, Natalie J.
    et al.
    Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Bugyei-Twum, Antoinette
    Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Rakhit, Rishi
    Stanford Univ, Dept Chem & Syst Biol, Stanford, CA 94305 USA..
    Walsh, Patrick
    Univ Toronto, Dept Biochem, Hosp Sick Children, Mol Struct & Funct Program, 1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada..
    Sharpe, Simon
    Univ Toronto, Dept Biochem, Hosp Sick Children, Mol Struct & Funct Program, 1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada..
    Arslan, Pharhad Eli
    Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Higaki, Jeffrey N.
    Prothena Biosci Inc, Dept Biochem, San Francisco, CA 94080 USA.;Prothena Biosci Inc, Dept Histopathol, San Francisco, CA 94080 USA..
    Torres, Ronald
    Prothena Biosci Inc, Dept Biochem, San Francisco, CA 94080 USA.;Prothena Biosci Inc, Dept Histopathol, San Francisco, CA 94080 USA..
    Tapia, Jose
    Prothena Biosci Inc, Dept Biochem, San Francisco, CA 94080 USA.;Prothena Biosci Inc, Dept Histopathol, San Francisco, CA 94080 USA..
    Chakrabartty, Avijit
    Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 25080Article in journal (Refereed)
    Abstract [en]

    Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis (R) and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentration is in the micromolar range. By immune-targeting sparsely populated TTR misfolding intermediates (i.e. monomers), we achieved fibril inhibition at substoichiometric concentrations. We developed an antibody (misTTR) that targets TTR residues 89-97, an epitope buried in the tetramer but exposed in the monomer. Nanomolar misTTR inhibits fibrillogenesis of misfolded TTR under micromolar concentrations. Pan-specific TTR antibodies do not possess such fibril inhibiting properties. We show that selective targeting of misfolding intermediates is an alternative to native state stabilization and requires substoichiometric concentrations. MisTTR or its derivative may have both diagnostic and therapeutic potential.

  • 17.
    Galant, Natalie J.
    et al.
    Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Dept Med Biophys, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Higaki, Jeffrey N.
    Prothena Biosci Inc, San Francisco, CA 94080 USA..
    Chakrabartty, Avijit
    Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Dept Med Biophys, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Transthyretin amyloidosis: an under-recognized neuropathy and cardiomyopathy2017In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 131, no 5, p. 395-409Article, review/survey (Refereed)
    Abstract [en]

    Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is an underdiagnosed and important type of cardiomyopathy and/or polyneuropathy that requires increased awareness within the medical community. Raising awareness among clinicians about this type of neuropathy and lethal form of heart disease is critical for improving earlier diagnosis and the identification of patients for treatment. The following review summarizes current criteria used to diagnose both hereditary and wild-type ATTR (ATTRwt) amyloidosis, tools available to clinicians to improve diagnostic accuracy, available and newly developing therapeutics, as well as a brief biochemical and biophysical background of TTR amyloidogenesis.

  • 18. Gustafsson, Sandra
    et al.
    Ihse, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Henein, Michael Y.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lindqvist, Per
    Suhr, Ole B.
    Amyloid Fibril Composition as a Predictor of Development of Cardiomyopathy After Liver Transplantation for Hereditary Transthyretin Amyloidosis2012In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 93, no 10, p. 1017-1023Article in journal (Refereed)
    Abstract [en]

    Background. Liver transplantation (LTx) is an accepted treatment for hereditary transthyretin (TTR) amyloidosis (ATTR). However, unforeseen heart complications, especially a rapid development of cardiomyopathy after LTx has affected mortality and morbidity. Recently, a relationship between ATTR-fibril composition and cardiomyopathy has been noted. The aim of this study was to investigate whether development of cardiomyopathy and heart failure in LTx ATTR amyloid patients is related to amyloid fibril composition.

    Methods. Twenty-four patients with hereditary ATTR amyloidosis who had undergone LTx and have had their amyloid fibril type tested were available for the study. They had been examined by echocardiography including tissue Doppler and speckle tracking echocardiography before and after LTx. Patients were divided into two groups according to fibril composition, 10 patients with type A fibrils (a mixture of truncated and full-length TTR) and 14 patients with type B fibrils (full-length TTR fibrils only). There was no difference in time to the follow-up echocardiography between the two groups.

    Results. After LTx, the group consisting of type A patients developed symptoms of heart failure and with reduced systolic and diastolic ventricular function as shown by echocardiography, whereas no similar deterioration was noted for the group of patients with type B fibrils.

    Conclusion. Patients with type A fibrils deteriorate an already existing cardiomyopathy and heart failure after LTx, in contrast to patients with type B fibrils. These results might have significant clinical implications in optimizing best patients selection criteria for LTx.

  • 19.
    Gustavsson, S.
    et al.
    Umea Univ, Clin Physiol & Heart Ctr, Umea, Sweden.;Umea Univ, Publ Hlth & Clin Med, Umea, Sweden..
    Pilebro, B.
    Umea Univ, Ctr Heart, Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lindqvist, P.
    Umea Univ, Ctr Heart, Umea, Sweden.;Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden..
    Suhr, O. B.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Gender related differences in cardiac function in patients with hereditary transthyretin amyloidosis2015In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 17, p. 64-65Article in journal (Other academic)
  • 20.
    Gånemo, Agneta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pigg, Maritta
    Virtanen, Marie
    Kukk, Terje
    Raudsepp, Heli
    Rossman-Ringdahl, Ingrid
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Niemi, Kirsti-Maria
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Autosomal recessive congenital ichthyosis in Sweden and Estonia: clinical, genetic and ultrastructural findings in eithty-three patients2003In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 83, no 1, p. 24-30Article in journal (Refereed)
    Abstract [en]

    Congenital (non-bullous) ichthyosis is a rare group of keratinizing disorders which can be tentatively subclassified based on clinical criteria, analysis of transglutaminase 1 gene mutations and electron microscopy of epidermis. We studied 83 patients who were all on topical therapy and in 16 cases also on oral retinoids. Three main groups of patients were distinguished: (A) those with transglutaminase 1 gene mutations (n=44), (B) those without transglutaminase 1 gene mutations showing a coarse, generalized scaling (n=19), and (C) those without transglutaminase 1 gene mutations showing only fine or focal scaling (n=20). On clinical scoring, patients in group A were more hyperkeratotic and less erythematous than those in group B (p < 0.05). Anhidrosis was recorded in nearly all patients (> or = 80%), but ectropion and a collodion phenotype at birth were more common in group A versus other groups. Ultrastructurally, a high frequency of type I (Anton-Lamprecht's classification) was found in all three groups (37-63%), 20 cases of type II in group A and a few cases of types III and IV in groups B and C, respectively. In conclusion, transglutaminase 1 gene mutation is a major cause of congenital ichthyosis in Sweden and Estonia, and is often associated with severe scaling and ultrastructural type II in corneocytes. The transglutaminase-unrelated cases are more heterogeneous, probably reflecting a more varied aetiology.

  • 21. Heegaard, Niels H H
    et al.
    Hansen, Morten Z
    Sen, Jette W
    Christiansen, Michael
    Westermark, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Immunoaffinity chromatographic and immunoprecipitation methods combined with mass spectrometry for characterization of circulating transthyretin.2006In: J Sep Sci, ISSN 1615-9306, Vol. 29, no 3, p. 371-7Article in journal (Refereed)
  • 22.
    Hellman, Urban
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Lang, Kenneth
    Piteå Hosp, Dept Med, Piteå, Sweden.
    Ihse, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Jonasson, Jenni
    Umea Univ, Dept Med Biosci Med & Clin Genet, Lab Med, Clin Genet, Umea, Sweden.
    Olsson, Malin
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden;Umea Univ, Wallenberg Ctr Mol Med, Umea, Sweden.
    Lundgren, Hans-Erik
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Pilebro, Bjorn
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden.
    Wixner, Jonas
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Anan, Intissar
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden;Umea Univ, Wallenberg Ctr Mol Med, Umea, Sweden.
    Transthyretin Glu54Leu-an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 6, p. 372-376Article in journal (Refereed)
    Abstract [en]

    For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.

  • 23. Hellman, Urban
    et al.
    Lundgren, Hans-Erik
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Stafberg, Christina
    Nahi, Hareth
    Tachlinski, Sascha
    Guggi, Michael
    Flogegard, Max
    Hamid, Mehmet
    Escher, Stefan A.
    Suhr, Ole B.
    A genealogical and clinical study of the phenotypical variation within the Swedish transthyretin His88Arg (p. His108Arg) amyloidosis family2015In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 58, no 4, p. 211-215Article in journal (Refereed)
    Abstract [en]

    In 2005 we reported the first case of transthyretin His88Arg (p. His108Arg) amyloidosis, a mutation characterised by cardiomyopathy. Six additional gene carriers of whom five have clinical symptoms of disease have now been identified in Sweden, and we have been able to identify a possible founder and to characterise the Swedish phenotype of the transthyretin (TTR) His88Arg mutation. Genealogical studies of church records were used to identify the individuals with the disease and their families. Routine clinical investigations of neurological and heart manifestation of the disease were utilised. We found that genealogically all seven individuals were related and originated from the same region in Sweden. Amyloid deposits were demonstrated in biopsies and the TTR His88Arg mutation was identified in all patients. Patients had a late onset disease (similar to 50 years of age) and all exhibited a severe amyloid cardiomyopathy. A pronounced peripheral axonal neuropathy was with certainty demonstrated in one patient only, who also was operated for a magnetic resonance confirmed spinal stenosis, however, without any effect on his neurological symptoms. Five of the patients had carpal tunnel syndrome. The first reported case is now deceased from cardiac failure. One patient has had a sequential heart and liver transplantation. One gene carrier had no symptoms or findings of disease on latest evaluation at the age of 44. In conclusion: the Swedish TTRHis88Arg patients all have a common Swedish founder. Cardiomyopathy with heart failure, as well as carpal tunnel syndrome and spinal stenosis were early signs of disease; but peripheral neuropathy was present in one patient before symptoms of cardiomyopathy so the phenotypical presentation of this mutation is variable.

  • 24.
    Hellstrom-Lindahl, Ewa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    In vitro binding of [H-3]PIB to human amyloid deposits of different types2014In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 21, no 1, p. 21-27Article in journal (Refereed)
    Abstract [en]

    Systemic amyloidosis is caused by extracellular deposition of insoluble fibrillar proteins arranged in beta-pleated sheets. [C-11] PIB has been used in PET studies to assess A beta deposition in brain of patients with Alzheimer's disease (AD). The possibility to visualize other types of amyloid deposits with [C-11] PIB would be of potential clinical importance in early diagnosis and for following therapeutic effects. In the present study, we evaluated in vitro binding of [3 H] PIB to tissues containing transthyretin (ATTR), immunoglobulin light-chain (AL), amyloid protein A (AA) and Ab amyloid. We found significantly higher binding of [H-3] PIB in tissue from systemic amyloidoses than in control tissue, i.e. 4.7 times higher (p<0.05). [H-3] PIB showed the highest affinity to cortex of AD brain (IC50 = 3.84 nM), while IC50 values were much higher for ATTR, AA and AL type of amyloidosis and large variations in affinity were observed even within tissues having the same type of amyloidosis. Extraction with guanidine-HCl, which disrupts the beta-sheet structure, decreased the protein levels and, concomitantly, the binding of [H-3] PIB in all four types of amyloidoses.

  • 25.
    Henein, Michael Y.
    et al.
    Umea Univ, Publ Hlth & Clin Med, Umea, Sweden.
    Suhr, Ole B.
    Umea Univ, Publ Hlth & Clin Med, Umea, Sweden.
    Arvidsson, Sandra
    Umea Univ, Ctr Heart, Clin Physiol, Umea, Sweden.
    Pilebro, Björn
    Umea Univ, Publ Hlth & Clin Med, Umea, Sweden.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hörnsten, Rolf
    Umea Univ, Ctr Heart, Clin Physiol, Umea, Sweden.
    Lindqvist, Per
    Umea Univ, Publ Hlth & Clin Med, Umea, Sweden.
    Reduced left atrial myocardial deformation irrespective of cavity size: a potential cause for atrial arrhythmia in hereditary transthyretin amyloidosis2018In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 25, no 1, p. 46-53Article in journal (Refereed)
    Abstract [en]

    Background: Cardiac amyloidosis (CA) is a myocardial disease and commonly under-diagnosed condition. In CA patients, atrial fibrillation might occur in the absence of left atrial (LA) enlargement.

    Objectives: The aim of this study is to assess LA size and function, and its relationship with atrial arrhythmia in patients with hereditary transthyretin amyloidosis (ATTR).

    Methods: Forty-six patients with confirmed ATTR amyloidosis on abdominal biopsy were studied. Assessment with 2D echocardiography and 2D strain showed 31 patients had increased LV wall thickness (LVWT) (septal thickness >12mm), and 15 had normal LVWT. In addition to conventional measurements, LV and LA global longitudinal strain (GLS%) and strain rate (SR) were obtained. Western blot analysis was done to assess fibril type. ATTR patients with increased LVWT were compared with 23 patients with hypertrophic cardiomyopathy (HCM) and 31 healthy controls. ATTR amyloidosis patients also underwent 24hour Holter monitoring to determine the presence of atrial arrhythmia.

    Results: Atrial deformation during atrial systole was reduced in ATTR amyloidosis patients with increased LVWT independent of LA size and in contrast to HCM. Twenty of the ATTR amyloidosis patients (54%) had ECG evidence of significant atrial arrhythmic events. LA strain rate, during atrial systole, was the only independent predictor of atrial arrhythmia (=3.28, p=.012).

    Conclusion: In ATTR cardiomyopathy with increased LVWT, LA myocardial function is abnormal, irrespective of atrial cavity size. Reduced LA myocardial SR during atrial systole, irrespective of cavity volume, E/e and LV deformation, is also a strong predictor for atrial arrhythmic events.

  • 26. Holmgren, Gasta
    et al.
    Hellman, Urban
    Jonasson, Jenni
    Lundgren, Hans-Eric
    Westermark, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Suhr, Ole B
    A Swedish family with the rare Phe33Leu transthyretin mutation.2005In: Amyloid, ISSN 1350-6129, Vol. 12, no 3, p. 189-92Article in journal (Refereed)
  • 27.
    Ihse, E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ybo, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Suhr, Ob
    Lindqvist, P
    Backman, C
    Westermark, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis2008In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 216, no 2, p. 253-61Article in journal (Refereed)
    Abstract [en]

    Swedish familial systemic amyloidosis with polyneuropathy (FAP) depends on a mutation leading to a methionine-for-valine substitution in transthyretin. The disease appears with different clinical manifestations, including age of onset and involvement of the heart. Liver transplantation is currently the only curative treatment, but progressive cardiomyopathy may occur post-transplant. Two amyloid deposition patterns have previously been described in the heart. In one, the amyloid consists partially of transthyretin fragments and is weakly stainable by Congo red, while in the other, only full-length molecules are found and the fibrils have a strong affinity for Congo red. The present study aimed to see whether these morphological and biochemical variations have clinical implications. Subcutaneous adipose tissue biopsies were taken from 33 patients with Val30Met FAP and examined by microscopy, electrophoresis and western blot. Clinical data included age, sex, duration of disease and echocardiographic determination of the interventricular septum (IVS) thickness. It was found that fibrils composed of only full-length transthyretin were associated with early age of onset (44.8 +/- 12.9 years), no clinical cardiac involvement and a strong affinity for Congo red. In contrast, presence of transthyretin fragments in the amyloid was associated with late age of onset (67.3 +/- 7.0 years), signs of cardiac involvement and weak Congo red staining. For each individual, the same molecular type of amyloid was found in different organs. This is the first report showing that variations in clinical appearance of familial ATTR amyloidosis are associated with specific structural differences in the amyloid fibrils, and therefore may have a molecular cause. The molecular type of amyloid can be determined from a subcutaneous fat tissue biopsy.

  • 28.
    Ihse, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rapezzi, Claudio
    Merlini, Giampaolo
    Benson, Merrill D.
    Ando, Yukio
    Suhr, Ole B.
    Ikeda, Shu-ichi
    Lavatelli, Francesca
    Obici, Laura
    Quarta, Candida C.
    Leone, Ornella
    Jono, Hirofumi
    Ueda, Mitsuharu
    Lorenzini, Massimiliano
    Liepnieks, Juris
    Ohshima, Toshinori
    Tasaki, Masayoshi
    Yamashita, Taro
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis2013In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 20, no 3, p. 142-150Article in journal (Refereed)
    Abstract [en]

    The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one consisting of mainly intact ATTR (type B). The fibril types are correlated to phenotypic differences. Patients with ATTR fragments have a late onset and develop cardiomyopathy, while patients without fragments have an early onset and less myocardial involvement. The present study aimed to determine whether this correlation between fibril type and phenotype is valid for familial ATTR amyloidosis in general. Cardiac or adipose tissues from 63 patients carrying 29 different TTR non-V30M mutations as well as 13 Japanese ATTRV30M patients were examined. Fibril type was determined by western blotting and compared to the patients' age of onset and degree of cardiomyopathy. All ATTR non-V30M patients had a fibril composition with ATTR fragments, except two ATTRY114C patients. No clear conclusions could be drawn about a phenotype to fibril type correlation among ATTR non-V30M patients. In contrast, Japanese ATTRV30M patients showed a similar correlation as previously described for Swedish ATTRV30M patients. This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis, and suggests that fibrils composed of only full-length ATTR is an exception found only in a subset of patients.

  • 29.
    Ihse, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stangou, Arie J.
    Heaton, Nigel D.
    O'Grady, John
    Ybo, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Edvinsson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Proportion between wild-type and mutant protein in truncated compared to full-length ATTR: an analysis on transplanted transthyretin T60A amyloidosis patients2009In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 379, no 4, p. 846-850Article in journal (Refereed)
    Abstract [en]

    Familial ATTR amyloidosis is caused by point mutations in the transthyretin gene. The clinical manifestations are highly varied but polyneuropathy and/or cardiomyopathy are generally the main symptoms. The amyloid fibrils can either be composed of only intact ATTR molecules or intact together with fragmented ATTR species. As plasma TTR is almost exclusively synthesized in the liver, liver transplantation is performed in order to eliminate the mutant plasma TTR. The procedure has shown best results among patients with the V30M mutation, while a rapid continued cardiac deposition of wild-type (wt) TTR has been seen for many other mutations. In this paper we investigated the proportion of wtATTR in two TTRT60A patients that underwent liver transplantation; one patient died 3 weeks after surgery, the other patient survived for 12 months. As the role of fragmented TTR species in the pathogenesis is far from understood, we investigated the proportion of wt in these species separately to the full-length molecules, which has not been done before in transplanted patients. The results show a higher proportion of wtTTR in the 12-months-surviving patient than the 3-weeks-surviving patient, but interestingly this difference in wt proportion is mainly seen among the full-length, and not the fragmented, molecules.

  • 30.
    Ihse, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Suhr, Ole B.
    Department of Internal Medicine, Umeå University, 901 85, Umeå, Sweden.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Variation in amount of wild-type transthyretin in different fibril and tissue types in ATTR amyloidosis2011In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 89, no 2, p. 171-180Article in journal (Refereed)
    Abstract [en]

    Familial transthyretin (TTR) amyloidosis is caused by a mutation in the TTR gene, although wild-type (wt) TTR is also incorporated into the amyloid fibrils. Liver transplantation (LT) is the prevailing treatment of the disease and is performed in order to eliminate the mutant TTR from plasma. The outcome of the procedure is varied; especially problematic is a progressive cardiomyopathy seen in some patients, presumably caused by continued incorporation of wtTTR. What determines the discrepancy in outcome is not clear. We have previously shown that two structurally distinct amyloid fibrils (with or without fragmented ATTR) are found among ATTRV30M patients. In this study, we investigated the proportion of wtATTR in cardiac and adipose amyloid from patients having either fibril type. It was found that cardiac amyloid more easily incorporates wtTTR than adipose amyloid, offering a potential explanation for the vulnerability of cardiac tissue for continued amyloidosis after LT. In cardiac tissue, fibrils with fragmented ATTR contained a higher wt proportion than fibrils without, suggesting that continued incorporation of wtTTR after LT, perhaps, can take place more easily in these patients. In adipose tissue, a rapid increase in wt proportion after LT indicates that a rather fast turnover of the deposits must occur. A difference in wt proportion between the fibril types was seen post-LT but not pre-LT, possibly caused by differences in turnover rate. Conclusively, this study further establishes the basic dissimilarities between the two fibril types and demonstrates that their role in LT outcome needs to be further investigated.

  • 31.
    Jansson, Desiree S.
    et al.
    Natl Vet Inst SVA, Dept Anim Hlth & Antimicrobial Strategies, Uppsala, Sweden..
    Bröjer, Caroline
    Natl Vet Inst SVA, Dept Pathol & Wildlife Dis, Uppsala, Sweden..
    Neimanis, Aleksija
    Natl Vet Inst SVA, Dept Pathol & Wildlife Dis, Uppsala, Sweden..
    Mörner, Torsten
    Natl Vet Inst SVA, Dept Dis Control & Epidemiol, Uppsala, Sweden..
    Murphy, Charles L.
    Univ Tennessee, Med Ctr, Dept Med, Knoxville, TN USA..
    Otman, Faruk
    Natl Vet Inst SVA, Dept Anim Hlth & Antimicrobial Strategies, Uppsala, Sweden..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Post mortem findings and their relation to AA amyloidosis in free-ranging Herring gulls (Larus argentatus)2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 3, article id e0193265Article in journal (Refereed)
    Abstract [en]

    Since the late 1990s, high mortality and declining populations have been reported among sea birds including Herring gulls ( Larus argentatus) from the Baltic Sea area in Northern Europe. Repeated BoNT type C/D botulism outbreaks have occurred, but it remains unclear whether this is the sole and primary cause of mortality. Thiamine deficiency has also been suggested as a causal or contributing factor. With this study, we aimed to investigate gross and microscopic pathology in Herring gulls from affected breeding sites in Sweden in search of contributing diseases. Herring gulls from Iceland served as controls. Necropsies and histopathology were performed on 75 birds, of which 12 showed signs of disease at the time of necropsy. Parasites of various classes and tissues were commonly observed independent of host age, e.g. oesophageal capillariosis and nematode infection in the proventriculus and gizzard with severe inflammation, air sac larid pentastomes and bursal trematodiasis in pre-fledglings. Gross and microscopic findings are described. Notably, amyloidosis was diagnosed in 93 and 33% of the adult birds from Sweden and Iceland, respectively ( p<0.001), with more pronounced deposits in Swedish birds ( p<0.001). Gastrointestinal deposits were observed in the walls of arteries or arterioles, and occasionally in villi near the mucosal surface. Amyloid was identified within the intestinal lumen in one severely affected gull suggesting the possibility of oral seeding and the existence of a primed state as previously described in some mammals and chickens. This could speculatively explain the high occurrence and previously reported rapid onset of amyloidosis upon inflammation or captivity in Herring gulls. Amyloid-induced malabsorbtion is also a possibility. The Herring gull SAA/AA protein sequence was shown to be highly conserved but differed at the N-terminus from other avian species.

  • 32. Jurgens, Catherine A.
    et al.
    Toukatly, Mirna N.
    Fligner, Corinne L.
    Udayasankar, Jayalakshmi
    Subramanian, Shoba L.
    Zraika, Sakeneh
    Aston-Mourney, Kathryn
    Carr, Darcy B.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kahn, Steven E.
    Hull, Rebecca L.
    beta-Cell Loss and beta-Cell Apoptosis in Human Type 2 Diabetes Are Related to Islet Amyloid Deposition2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 178, no 6, p. 2632-2640Article in journal (Refereed)
    Abstract [en]

    Amyloid deposition and reduced beta-cell mass are pathological hallmarks of the pancreatic islet in type 2 diabetes; however, whether the extent of amyloid deposition is associated with decreased beta-cell mass is debated. We investigated the possible relationship and, for the first time, determined whether increased islet amyloid and/or decreased beta-cell area quantified on histological sections is correlated with increased beta-cell apoptosis. Formalin-fixed, paraffin-embedded human pancreas sections from subjects with (n = 29) and without (n = 39) diabetes were obtained at autopsy (64 +/- 2 and 70 +/- 4 islets/subject, respectively). Amyloid and beta cells were visualized by thioflavin S and insulin inununolabeling. Apoptotic beta cells were detected by colabeling for insulin and by TUNEL. Diabetes was associated with increased amyloid deposition, decreased beta-cell area, and increased beta-cell apoptosis, as expected. There was a strong inverse correlation between beta-cell area and amyloid deposition (r = -0.42, P < 0.001). beta-Cell area was selectively reduced in individual amyloid-containing islets from diabetic subjects, compared with control subjects, but amyloid-free islets had beta-cell area equivalent to islets from control subjects. Increased amyloid 'deposition was associated with beta-cell apoptosis (r = 0.56, P < 0.01). Thus, islet amyloid is associated with decreased beta-cell area and increased beta-cell apoptosis, suggesting that islet amyloid deposition contributes to the decreased beta-cell mass that characterizes type 2 diabetes.

  • 33.
    Kollmer, Marius
    et al.
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Meinhardt, Katrin
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Haupt, Christian
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Liberta, Falk
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Wulff, Melanie
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Linder, Julia
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Handl, Lisa
    Univ Ulm, Inst Stochast, D-89081 Ulm, Germany..
    Heinrich, Liesa
    Hans Knoell Inst, Leibniz Inst Nat Prod Res & Infect Biol, D-07745 Jena, Germany..
    Loos, Cornelia
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Schmidt, Matthias
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Syrovets, Tatiana
    Univ Ulm, Inst Pharmacol Nat Prod & Clin Pharmacol, D-89081 Ulm, Germany..
    Simmet, Thomas
    Univ Ulm, Inst Pharmacol Nat Prod & Clin Pharmacol, D-89081 Ulm, Germany..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Horn, Uwe
    Hans Knoell Inst, Leibniz Inst Nat Prod Res & Infect Biol, D-07745 Jena, Germany..
    Schmidt, Volker
    Univ Ulm, Inst Stochast, D-89081 Ulm, Germany..
    Walther, Paul
    Univ Ulm, Cent Electron Microscopy Facil, D-89081 Ulm, Germany..
    Faendrich, Marcus
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Electron tomography reveals the fibril structure and lipid interactions in amyloid deposits2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 20, p. 5604-5609Article in journal (Refereed)
    Abstract [en]

    Electron tomography is an increasingly powerful method to study the detailed architecture of macromolecular complexes or cellular structures. Applied to amyloid deposits formed in a cell culture model of systemic amyloid A amyloidosis, we could determine the structural morphology of the fibrils directly in the deposit. The deposited fibrils are arranged in different networks, and depending on the relative fibril orientation, we can distinguish between fibril meshworks, fibril bundles, and amyloid stars. These networks are frequently infiltrated by vesicular lipid inclusions that may originate from the death of the amyloid-forming cells. Our data support the role of nonfibril components for constructing fibril deposits and provide structural views of different types of lipid-fibril interactions.

  • 34.
    Larsson, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Malmström, Susanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Signs of cross-seeding: aortic medin amyloid as a trigger for protein AA deposition2011In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 18, no 4, p. 229-234Article in journal (Refereed)
    Abstract [en]

    The highly diverse deposition pattern displayed by systemic amyloidoses, sometimes within the same amyloid disease, remains unexplained. The localized medin (AMed) amyloidosis develops from the precursor protein lactadherin and deposits in the media of the thoracic aorta in almost all individuals above 50 years of age. Given its high prevalence in the population, and the fact that systemic amyloidoses also deposit in the aorta, led us to investigate whether AMed amyloid could influence the tissue distribution of serum amyloid A derived (AA) amyloidosis. Seven aortas from patients with diagnosed systemic AA amyloidosis were investigated. Four displayed partial co-localization between medin and AA aggregates when examined with double-labeling immunofluorescence. Furthermore, in vitro studies showed that AMed amyloid-like fibrils promote the aggregation of protein AA into fibrils. The findings indicate that the highly frequent "senile" amyloidoses may have the potential to initiate fibril formation of the more uncommon amyloidoses by a cross-seeding mechanism.

  • 35.
    Larsson, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Peng, Siwei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Persson, Helena
    Rosenbloom, Joel
    Abrams, William R.
    Wassberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Thelin, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sletten, Knut
    Gerwins, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lactadherin binds to elastin -a starting point for medin amyloid formation?2006In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 13, no 2, p. 78-85Article in journal (Refereed)
    Abstract [en]

    Medin amyloid is found in the medial layer of the aorta in almost 100% of the Caucasian population over 50 years of age. The medin fragment is 5.5 kDa and derives from the C2-like domain of the precursor protein lactadherin. We have previously reported immunohistochemical findings showing that medin amyloid co-localizes with elastic fibers of arteries and herein we show that lactadherin also is associated with elastic structures of human aortic material. In addition, results from in vitro binding assays demonstrate that both medin and lactadherin bind to tropoelastin in a concentration-dependent fashion, suggesting that the lactadherin-tropoelastin interaction is mediated via the medin domain. It is possible that lactadherin, which is a cell adhesion protein, in this way connects smooth muscle cells to the elastic fibers of arteries. Given that both medin and lactadherin interact with elastic fibers, elastin is probably an important component in the formation of medin amyloid.

  • 36.
    Larsson, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Söderberg, Linda
    Westermark, Gunilla T.
    Sletten, Knut
    Engström, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Tjernberg, Lars O.
    Näslund, Jan
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Unwinding fibril formation of medin, the peptide of the most common form of human amyloid.2007In: 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.

  • 37.
    Liberta, Falk
    et al.
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Loerch, Sarah
    Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA.
    Rennegarbege, Matthies
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Schierhorn, Angelika
    Martin Luther Univ Halle Wittenberg, Inst Biochem & Biotechnol, D-06120 Halle, Saale, Germany.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Westermark, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hazenberg, Bouke P. C.
    Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, NL-9700 RB Groningen, Netherlands.
    Grigorieff, Nikolaus
    Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA.
    Faendrich, Marcus
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Schmidt, Matthias
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 1104Article in journal (Refereed)
    Abstract [en]

    Systemic AA amyloidosis is a worldwide occurring protein misfolding disease of humans and animals. It arises from the formation of amyloid fibrils from the acute phase protein serum amyloid A. Here, we report the purification and electron cryo-microscopy analysis of amyloid fibrils from a mouse and a human patient with systemic AA amyloidosis. The obtained resolutions are 3.0 angstrom and 2.7 angstrom for the murine and human fibril, respectively. The two fibrils differ in fundamental properties, such as presence of right-hand or left-hand twisted cross-beta sheets and overall fold of the fibril proteins. Yet, both proteins adopt highly similar beta-arch conformations within the N-terminal similar to 21 residues. Our data demonstrate the importance of the fibril protein N-terminus for the stability of the analyzed amyloid fibril morphologies and suggest strategies of combating this disease by interfering with specific fibril polymorphs.

  • 38. Linke, Reinhold P
    et al.
    Joswig, Reinhild
    Murphy, Charles L
    Wang, Shuching
    Zhou, Hui
    Gross, Ulrich
    Rocken, Christoph
    Westermark, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Weiss, Deborah T
    Solomon, Alan
    Senile seminal vesicle amyloid is derived from semenogelin I.2005In: J Lab Clin Med, ISSN 0022-2143, Vol. 145, no 4, p. 187-93Article in journal (Refereed)
  • 39. Lundmark, Katarzyna
    et al.
    Westermark, Gunilla T
    Olsen, Arne
    Westermark, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism.2005In: Proc Natl Acad Sci U S A, ISSN 0027-8424, Vol. 102, no 17, p. 6098-102Article in journal (Refereed)
  • 40. Ma, Z
    et al.
    Westermark, GT
    Sakagashira, S
    Sanke, T
    Gustavsson, Å
    Sakamoto, H
    Engström, Ulla
    Ludwiginstitutet för Cancerforskning.
    Nanjo, K
    Westermark, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Enhanced in vitro production of amyloid-like fibrils from mutant (S20G) islet amyloid polypeptide2001In: Amyloid, Vol. 8, p. 242-Article 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 (IAPPwt) 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 Tfluorometric 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.

  • 41.
    Noborn, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    O'Callaghan, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hermansson, Erik
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ancsin, John
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Damas, Ana
    Dacklin, Ingrid
    Presto, Jenny
    Johansson, Jan
    Saraiva, Maria
    Lundgren, Erik
    Kisilevsky, Robert
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Li, Jin-ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 14, p. 5584-5589Article in journal (Refereed)
    Abstract [en]

    Transthyretin (TTR) is a homotetrameric protein that transports thyroxine and retinol. Tetramer destabilization and misfolding of the released monomers result in TTR aggregation, leading to its deposition as amyloid primarily in the heart and peripheral nervous system. Over 100 mutations of TTR have been linked to familial forms of TTR amyloidosis. Considerable effort has been devoted to the study of TTR aggregation of these mutants, although the majority of TTR-related amyloidosis is represented by sporadic cases due to the aggregation and deposition of the otherwise stable wild-type (WT) protein. Heparan sulfate (HS) has been found as a pertinent component in a number of amyloid deposits, suggesting its participation in amyloidogenesis. This study aimed to investigate possible roles of HS in TTR aggregation. Examination of heart tissue from an elderly cardiomyopathic patient revealed substantial accumulation of HS associated with the TTR amyloid deposits. Studies demonstrated that heparin/HS promoted TTR fibrillization through selective interaction with a basic motif of TTR. The importance of HS for TTR fibrillization was illustrated in a cell model; TTR incubated with WT Chinese hamster ovary cells resulted in fibrillization of the protein, but not with HS-deficient cells (pgsD-677). The effect of heparin on TTR fibril formation was further demonstrated in a Drosophila model that overexpresses TTR. Heparin was colocalized with TTR deposits in the head of the flies reared on heparin-supplemented medium, whereas no heparin was detected in the nontreated flies. Heparin of low molecular weight (Klexane) did not demonstrate this effect.

  • 42.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Hall, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Hammarstrom, Per
    Nilsson, Peter R.
    Back, Marcus
    Johansson, Leif B. G.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    C-11 and F-18 radiolabeling of tetra and pentatiophenes as PET-ligands for misfolded protein aggregates2013In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 56, no S1, p. S35-S35Article in journal (Other academic)
  • 43.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Johansson, Leif B. G.
    Linkoping Univ, Dept Chem, IFM, S-58183 Linkoping, Sweden..
    Back, Marcus
    Linkoping Univ, Dept Chem, IFM, S-58183 Linkoping, Sweden..
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Hall, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Sjölander, Daniel
    Linkoping Univ, Dept Chem, IFM, S-58183 Linkoping, Sweden..
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Nilsson, Lars
    Univ Oslo, Dept Pharmacol, N-0316 Oslo, Norway..
    Hammarström, Per
    Linkoping Univ, Dept Chem, IFM, S-58183 Linkoping, Sweden..
    Nilsson, K. Peter R.
    Linkoping Univ, Dept Chem, IFM, S-58183 Linkoping, Sweden..
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    C-11 and F-18 Radiolabeling of Tetra- and Pentathiophenes as PET-Ligands for Amyloid Protein Aggregates2016In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 7, no 4, p. 368-373Article in journal (Refereed)
    Abstract [en]

    Three oligothiophenes were evaluated as PET ligands for the study of local and systemic amyloidosis ex vivo using tissue from patients with amyloid deposits and in vivo using healthy animals and PET-CT. The ex vivo binding studies revealed that all three labeled compounds bound specifically to human amyloid deposits. Specific binding was found in the heart, kidney, liver, and spleen. To verify the specificity of the oligothiophenes toward amyloid deposits, tissue sections with amyloid pathology were stained using the fluorescence exhibited by the compounds and evaluated with multiphoton microscopy. Furthermore, a in vivo monkey PET-CT study showed very low uptake in the brain, pancreas, and heart of the healthy animal indicating low nonspecific binding to healthy tissue. The biological evaluations indicated that this is a promising group of compounds for the visualization of systemic and localized amyloidosis.

  • 44.
    Nyström, Sofie
    et al.
    Linköping Univ.
    Panahi, Aida Vahdat Shariat
    Linköping Univ.
    Nilsson, K. Peter R.
    Linkoping Univ.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Westermark, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hammarstrom, Per
    Linköping Univ.
    Lundmark, Katarzyna
    Linköping Univ.
    Seed-dependent templating of murine AA amyloidosis2017In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, p. 140-141Article in journal (Other academic)
  • 45. Oshima, Toshinori
    et al.
    Kawahara, Satomi
    Ueda, Mitsuharu
    Kawakami, Yushi
    Tanaka, Rina
    Okazaki, Takahiro
    Misumi, Yohei
    Obayashi, Konen
    Yamashita, Taro
    Ohya, Yuki
    Ihse, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Shinriki, Satoru
    Tasaki, Masayoshi
    Jono, Hirofumi
    Asonuma, Katsuhiro
    Inomata, Yukihiro
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Ando, Yukio
    Changes in pathological and biochemical findings of systemic tissue sites in familial amyloid polyneuropathy more than 10 years after liver transplantation2014In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 85, no 7, p. 740-746Article in journal (Refereed)
    Abstract [en]

    Objective To elucidate the long-term effects of liver transplantation (LT) on familial amyloid polyneuropathy (FAP). Methods We investigated clinicopathological and biochemical characteristics of systemic tissues in four autopsied cases of FAP patients surviving more than 10 years after LT and seven autopsied cases without LT. For analysing the truncated form of transthyretin (TTR) in amyloid, we also employed specimens from additional 18 FAP patients. Results Several tissue sites such as the heart, tongue and spinal cord had moderate-to-severe amyloid deposits but other tissues showed no or mild amyloid deposition. Those findings seemed similar to those observed in senile systemic amyloidosis (SSA), a sporadic amyloidosis caused by wild-type (WT) TTR. Also, amyloid deposits in systemic tissue sites except for the spinal cord in patients after LT derived mostly from WT TTR secreted from the normal liver grafts. In addition, in non-transplantation patients, proportions of WT TTR seemed to be relatively high in those tissue sites in which patients after LT had severe amyloid deposition, which suggests that WT TTR tends to form amyloid in those tissue sites. Finally, although the truncation of TTR in amyloid deposits did not depend on undergoing LT, we elucidated the truncation of TTR occurred predominantly in patients from non-endemic areas of Japan, where FAP amyloidogenic TTR V30M patients are late onset and low penetrance, compared with patients from an endemic area of Japan. Conclusions FAP may shift to systemic WT TTR amyloid formation after LT, which seems to be similar to the process in SSA. The truncation of TTR in amyloid deposits may depend on some genetic or environmental factors other than undergoing LT.

  • 46.
    Oskarsson, Marie E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Paulsson, Johan F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Schultz, Sebastian W.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    In Vivo Seeding and Cross-Seeding of Localized Amyloidosis A Molecular Link between Type 2 Diabetes and Alzheimer Disease2015In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 185, no 3, p. 834-846Article in journal (Refereed)
    Abstract [en]

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

  • 47. Paulsson, J F
    et al.
    Andersson, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Westermark, P
    Department of Genetics and Pathology.
    Westermark, G T
    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 islets.2006In: Diabetologia, ISSN 0012-186X, Vol. 49, no 6, p. 1237-46Article in journal (Refereed)
  • 48. Peca, Donatella
    et al.
    Boldrini, Renata
    Johannson, Jan
    Shieh, Joseph T.
    Citti, Arianna
    Petrini, Stefania
    Salerno, Teresa
    Cazzato, Salvatore
    Testa, Raffaele
    Messina, Francesco
    Onofri, Alfredo
    Cenacchi, Giovanna
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ullmann, Nicola
    Cogo, Paola
    Cutrera, Renato
    Danhaive, Olivier
    Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations2015In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, no 8, p. 1033-1041Article in journal (Refereed)
    Abstract [en]

    Genetic defects of surfactant metabolism are associated with a broad range of clinical manifestations, from neonatal respiratory distress syndrome to adult interstitial lung disease. Early therapies may improve symptoms but diagnosis is often delayed owing to phenotype and genotype variability. Our objective was to characterize the cellular/ultrastructural correlates of surfactant protein C (SP-C) mutations in children with idiopathic diffuse lung diseases. We sequenced SFTPC - the gene encoding SP-C - SFTPB and ABCA3, and analyzed morphology, ultrastructure and SP expression in lung tissue when available. We identified eight subjects who were heterozygous for SP-C mutations. Median age at onset and clinical course were variable. None of the mutations were located in the mature peptide-encoding region, but were either in the pro-protein BRICHOS or linker C-terminal domains. Although lung morphology was similar to other genetic surfactant metabolism disorders, electron microscopy studies showed specific anomalies, suggesting surfactant homeostasis disruption, plus trafficking defects in the four subjects with linker domain mutation and protein misfolding in the single BRICHOS mutation carrier in whom material was available. Immunolabeling studies showed increased proSP-C staining in all cases. In two cases, amyloid deposits could be identified. Immunochemistry and ultrastructural studies may be useful for diagnostic purposes and for genotype interpretation.

  • 49.
    Peng, Siwei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Glennert, Johanna
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Medin-amyloid: a recently characterized age-associated arterial amyloid form affects mainly arteries in the upper part of the body2005In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 12, no 2, p. 96-102Article in journal (Refereed)
    Abstract [en]

    Amyloid deposition occurs commonly in the aging aortic media. We recently found that a 50 amino acid amyloid fibril protein, which we called medin, forms the fibrils of this amyloid form. Medin is an internal fragment of the 364 long precursor lactadherin, which is expressed by several kinds of cells including vascular smooth muscle cells. With the use of specific antibodies we have now studied the vascular distribution of medin (AMed) amyloid in a series of 18 individuals, 57 years of age and older. All individuals had widely spread AMed amyloid in the media of the thoracic aorta while this type of amyloid occurred less commonly in the abdominal aorta. In 8 of the 18 individuals, AMed-amyloid was also found in the basilar artery while the frequency was lower in other studied arteries. Amyloid was usually seen in close association with the internal elastic lamina. Analysis of proteins extracted from amyloid-rich aortic media showed presence of both lactadherin and medin. This study shows that AMed amyloid is not restricted to the aorta and the temporal artery but also occurs in other arteries, mainly in the upper part of the body. AMed amyloid has to be added to the forms of amyloid that may be seen in intracranial vessels.

  • 50.
    Peng, Siwei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Larsson, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wassberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Gerwins, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Thelin, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Fu, Xin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Role of aggregated medin in the pathogenesis of thoracic aortic aneurysm and dissection2007In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 87, no 12, p. 1195-1205Article in journal (Refereed)
    Abstract [en]

    The pathogenesis of sporadic thoracic aortic aneurysm and dissection, which may lead to rupture of the aorta, remains largely unknown. Amyloid deposits, formed from the medin peptide, are very prevalent in the media of the thoracic aorta. We have studied the occurrence of medin-derived amyloid in specimens from patients with thoracic aortic aneurysm, aortic dissection type A and normal dimensioned aorta. Surprisingly, the amount of amyloid was significantly lower in the aneurysm and dissection groups (0.63+/-0.13 and 0.36+/-0.24 amyloid particles per mm2, respectively) compared to the control material (2.37+/-0.58). However, focal medin immunoreactivity not associated with amyloid was found more conspicuously in the media of the two diseased groups. Recent amyloid research indicates that prefibrillar oligomeric aggregates, rather than mature amyloid fibrils, are toxic to the surrounding cells. The non-amyloid medin immunoreactivity observed may represent such toxic oligomers. This is supported by the fact that aggregated medin induced death of aortic smooth muscle cells in vitro. In addition, cells incubated together with medin increased the production of matrix metalloproteinase-2, a protease that degrades elastin and collagen and subsequently weakens the vessel wall. We therefore propose that medin oligomers are involved in the degeneration process of sporadic thoracic aortic aneurysm and dissection.

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