Logo: to the web site of Uppsala University

uu.sePublications from Uppsala University
Change search
Refine search result
123 1 - 50 of 124
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 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.

    Download full text (pdf)
    fulltext
  • 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, 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.

    Download full text (pdf)
    fulltext
  • 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 46202 USA..
    Berk, John L.
    Boston Univ, Sch Med, Amyloidosis Ctr, Boston, MA 02118 USA..
    Dispenzieri, Angela
    Mayo Clin, Div Hematol, Rochester, MN USA..
    Damy, Thibaud
    Henri Mondor Teaching Hosp, AP HP, Mondor Amyloidosis Network, Creteil, France.;Henri Mondor Teaching Hosp, AP HP, GRC Amyloid Res Inst, Creteil, France.;Henri Mondor Teaching Hosp, AP HP, Dept Cardiol, Creteil, France.;UPEC, Creteil, France..
    Gillmore, Julian D.
    UCL, Div Med, Natl Amyloidosis Ctr, Royal Free Campus, London, England..
    Hazenberg, Bouke P.
    Univ Groningen, Univ Med Ctr Groningen, Amyloidosis Ctr Expertise, Groningen, Netherlands..
    Lavatelli, Francesca
    IRCCS Policlin San Matteo, Amyloidosis Res & Treatment Ctr, Pavia, Italy.;Univ Pavia, Pavia, Italy..
    Picken, Maria M.
    Loyola Univ Med Ctr, Dept Pathol, Chicago, IL USA..
    Röcken, Christoph
    Univ Kiel, Univ Hosp Schleswig Holstein, Dept Pathol, Kiel, Germany..
    Schönland, Stefan
    Univ Hosp Heidelberg, Amyloidosis Ctr, Med Dept 5, Heidelberg, Germany..
    Ueda, Mitsuharu
    Kumamoto Univ, Dept Neurol, Amyloidosis Ctr, Kumamoto, Japan..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Tissue biopsy for the diagnosis of amyloidosis: experience from some centres2022In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 29, no 1, p. 8-13Article in journal (Refereed)
    Abstract [en]

    A reliable diagnosis of amyloidosis is usually based on a tissue biopsy. With increasing options for specific treatments of the different amyloid diseases, an exact and valid diagnosis including determination of the biochemical fibril nature is imperative. Biopsy sites as well as amyloid typing principles vary and this paper describes methods employed at some laboratories specialised in amyloidosis in Europe, Japan and USA.

    Download full text (pdf)
    fulltext
  • 8.
    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.

    Download full text (pdf)
    fulltext
  • 9.
    Benson, Merrill D.
    et al.
    Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA..
    Buxbaum, Joel N.
    Scripps Res Inst, Dept Mol Med, La Jolla, CA 92037 USA..
    Eisenberg, David S.
    Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA..
    Merlini, Giampaolo
    Fdn IRCCS Policlin San Matteo, Amyloid Res & Treatment Ctr, Pavia, Italy.;Univ Pavia, Pavia, Italy..
    Saraiva, Maria J. M.
    Univ Porto, Mol Neurobiol, Inst Mol & Cellular Biol, 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 02118 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 2020: update and recommendations by the International Society of Amyloidosis (ISA) nomenclature committee2020In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 27, no 4, p. 217-222Article in journal (Refereed)
    Abstract [en]

    The ISA Nomenclature Committee met electronically before and directly after the XVII ISA International Symposium on Amyloidosis, which, unfortunately, had to be virtual in September 2020 due to the ongoing COVID-19 pandemic instead of a planned meeting in Tarragona in March. In addition to confirmation of basic nomenclature, several additional concepts were discussed, which are used in scientific amyloid literature. Among such concepts are cytotoxic oligomers, protofibrils, primary and secondary nucleation, seeding and cross-seeding, amyloid signature proteins, and amyloid plaques. Recommendations for their use are given. Definitions of amyloid and amyloidosis are confirmed. Possible novel human amyloid fibril proteins, appearing as 'classical' in vivo amyloid, were discussed. It was decided to include fibulin-like extracellular matrix protein 1 (amyloid protein: AEFEMP1), which appears as localised amyloid in portal veins. There are several possible amyloid proteins under investigation, and these are included in a new Table.

    Download full text (pdf)
    fulltext
  • 10.
    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.

  • 11.
    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.

  • 12.
    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.

  • 13.
    Buxbaum, Joel N.
    et al.
    Scripps Res Inst, Dept Mol Med, Protego Biopharm San Diego, La Jolla, CA USA..
    Dispenzieri, Angela
    Mayo Clin, Div Hematol, Rochester, MN USA..
    Eisenberg, David S.
    Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA USA..
    Fändrich, Marcus
    Ulm Univ, Inst Prot Biochem, Ulm, Germany..
    Merlini, Giampaolo
    Fdn IRCCS Policlin San Matteo, Amyloid Res & Treatment Ctr, Pavia, Italy.;Univ Pavia, Pavia, Italy..
    Saraiva, Maria J. M.
    Univ Porto, Inst Mol & Cellular Biol, Mol Neurobiol, Porto, Portugal..
    Sekijima, Yoshiki
    Shinshu Univ, Dept Med Neurol & Rheumatol, Sch Med, Matsumoto, Japan..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Amyloid nomenclature 2022: update, novel proteins, and recommendations by the International Society of Amyloidosis (ISA) Nomenclature Committee2022In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 29, no 4, p. 213-219Article in journal (Refereed)
    Abstract [en]

    The Nomenclature Committee of the International Society of Amyloidosis met at the XVIII International Symposium on Amyloidosis in September and virtually in October 2022 with discussions resulting in this upgraded nomenclature recommendation. The nomenclature principles remain unchanged but there is an ongoing discussion regarding the importance and varying nature of intracellular protein aggregates, particularly those associated with neurodegenerative diseases. Six novel proteins were added to the list of human amyloid fibril proteins. Of these, three are polypeptide hormones and two currently utilised peptide drugs, making the number of known iatrogenic amyloid forms four, all appearing as subcutaneous nodules at the injection site. The sixth novel amyloid fibril protein is the transmembrane 106B protein, forming intracellular amyloid fibrils in disorders associated with frontotemporal dementia. The number of known human amyloid fibril proteins is now 42.

  • 14. 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.

  • 15.
    Canetti, Diana
    et al.
    UCL, Ctr Amyloidosis & Acute Phase Prot, Wolfson Drug Discovery Unit, Div Med, London, England..
    Nocerino, Paola
    UCL, Ctr Amyloidosis & Acute Phase Prot, Wolfson Drug Discovery Unit, Div Med, London, England..
    Rendell, Nigel B.
    UCL, Ctr Amyloidosis & Acute Phase Prot, Wolfson Drug Discovery Unit, Div Med, London, England..
    Botcher, Nicola
    UCL, Natl Amyloidosis Ctr, London, England.;Royal Free Hosp, London, England..
    Gilbertson, Janet A.
    UCL, Natl Amyloidosis Ctr, London, England.;Royal Free Hosp, London, England..
    Blanco, Angel
    UCL, Natl Amyloidosis Ctr, London, England.;Royal Free Hosp, London, England..
    Rowczenio, Dorota
    UCL, Natl Amyloidosis Ctr, London, England.;Royal Free Hosp, London, England..
    Morelli, Alessandra
    Univ Pavia, Dept Mol Med Inst Biochem, Pavia, Italy..
    Mangione, P. Patrizia
    UCL, Ctr Amyloidosis & Acute Phase Prot, Wolfson Drug Discovery Unit, Div Med, London, England.;Univ Pavia, Dept Mol Med Inst Biochem, Pavia, Italy..
    Corazza, Alessandra
    Univ Udine, Dept Med DAME, Udine, Italy..
    Verona, Guglielmo
    UCL, Ctr Amyloidosis & Acute Phase Prot, Wolfson Drug Discovery Unit, Div Med, London, England..
    Giorgetti, Sofia
    Univ Pavia, Dept Mol Med Inst Biochem, Pavia, Italy..
    Marchese, Loredana
    Univ Pavia, Dept Mol Med Inst Biochem, 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.
    Hawkins, Philip N.
    UCL, Natl Amyloidosis Ctr, London, England.;Royal Free Hosp, London, England..
    Gillmore, Julian D.
    UCL, Natl Amyloidosis Ctr, London, England.;Royal Free Hosp, London, England..
    Bellotti, Vittorio
    UCL, Ctr Amyloidosis & Acute Phase Prot, Wolfson Drug Discovery Unit, Div Med, London, England.;Univ Pavia, Dept Mol Med Inst Biochem, Pavia, Italy..
    Taylor, Graham W.
    UCL, Ctr Amyloidosis & Acute Phase Prot, Wolfson Drug Discovery Unit, Div Med, London, England..
    Clinical ApoA-IV amyloid is associated with fibrillogenic signal sequence2021In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 255, no 3, p. 311-318Article in journal (Refereed)
    Abstract [en]

    Apolipoprotein A-IV amyloidosis is an uncommon form of the disease normally resulting in renal and cardiac dysfunction. ApoA-IV amyloidosis was identified in 16 patients attending the National Amyloidosis Centre and in eight clinical samples received for histology review. Unexpectedly, proteomics identified the presence of ApoA-IV signal sequence residues (p.18-43 to p.20-43) in 16/24 trypsin-digested amyloid deposits but in only 1/266 non-ApoA-IV amyloid samples examined. These additional signal residues were also detected in the cardiac sample from the Swedish patient in which ApoA-IV amyloid was first described, and in plasma from a single cardiac ApoA-IV amyloidosis patient. The most common signal-containing peptide observed in ApoA-IV amyloid, p.20-43, and to a far lesser extent the N-terminal peptide, p.21-43, were fibrillogenic in vitro at physiological pH, generating Congo red-positive fibrils. The addition of a single signal-derived alanine residue to the N-terminus has resulted in markedly increased fibrillogenesis. If this effect translates to the mature circulating protein in vivo, then the presence of signal may result in preferential deposition as amyloid, perhaps acting as seed for the main circulating native form of the protein; it may also influence other ApoA-IV-associated pathologies. (c) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

  • 16.
    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)
  • 17.
    Damjanovic Vesterlund, Justina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala Univ Hosp, Clin Pathol, Uppsala, Sweden..
    Ihse, Elisabet
    Uppsala Univ Hosp, Clin Pathol, Uppsala, Sweden.;Uppsala Univ, Dept Genet Immunol & Pathol, Uppsala, Sweden..
    Thelander, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala Univ Hosp, Clin Pathol, Uppsala, Sweden..
    Zancanaro, Alice
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Westermark, Gunilla
    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, Neurooncology and neurodegeneration. Uppsala Univ Hosp, Clin Pathol, Uppsala, Sweden..
    Tissue-based diagnosis of systemic amyloidosis: Experience of the informal diagnostic center at Uppsala University Hospital2022In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 127, no 1, article id e8913Article in journal (Refereed)
    Abstract [en]

    Diagnosis of systemic amyloidosis is a clinical challenge and usually relies on a tissue biopsy. We have developed diagnostic methods based on the presence of amyloid deposits in abdominal subcutaneous fat tissue. This tissue is also used to determine the biochemical type of amyloidosis, performed by western blot and immunohistochemical analyses with the aid of in-house developed rabbit antisera and mouse monoclonal antibodies. Mass spectrometric methods are under development for selected cases. The diagnostic outcome for 2018-2020 was studied. During this period, we obtained 1,562 biopsies, of which 1,397 were unfixed subcutaneous fat tissue with varying degrees of suspicion of systemic amyloidosis. Of these, 440 contained amyloid deposits. The biochemical nature of the amyloid was determined by western blot analysis in 319 specimens and by immunohistochemistry in further 51 cases.

    Download full text (pdf)
    FULLTEXT01
  • 18.
    Eldhagen, P.
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Solna, Sweden..
    Berg, S.
    Lowenstramska Hosp, Stockholm Spine Ctr, Upplands Väsby, Sweden..
    Lund, L. H.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Solna, Sweden..
    Sorensson, P.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Solna, Sweden..
    Suhr, O. B.
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Transthyretin amyloid deposits in lumbar spinal stenosis and assessment of signs of systemic amyloidosis2021In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 289, no 6, p. 895-905Article in journal (Refereed)
    Abstract [en]

    Background. Wild-type transthyretin (ATTRwt) amyloidosis is the most common systemic amyloidosis in Western countries and manifests mainly as progressive restrictive cardiomyopathy.

    Objective. To study the prevalence of ATTR deposits in ligament tissue in patients undergoing surgery for lumbar spinal stenosis and to assess whether these deposits are associated with cardiac amyloidosis.

    Materials and methods. A total of 250 patients, aged 50-89 (57% women), none with known cardiovascular disease, were included. Ligaments were investigated microscopically for amyloid. ATTR type was determined by immunohistochemistry and fibril type by Western blot. The amount of amyloid was graded 0-4. All patients with grade 3-4 ATTR deposits were offered cardiac investigation including ECG, cardiac ultrasound, plasma NT-proBNP and cardiac magnetic resonance (CMR), including modern tissue characterization.

    Results. Amyloid was identified in 221 of the samples (88.4%). ATTR appeared in 93 samples (37%) of whom 42 (17 women and 25 men) were graded 3-4; all had fibril type A (mixture of full-length TTR and fragmented TTR). Twenty-nine of 42 patients with grade 3-4 ATTR deposits accepted cardiovascular investigations; none of them had definite signs of cardiac amyloidosis, but five men had a history of carpal tunnel syndrome.

    Conclusions. The prevalence of ATTR deposits in ligamentum flavum in patients with lumbar spinal stenosis was high but not associated with manifest ATTR cardiac amyloidosis. However, the findings of fibril type A, the prevalence of previous carpal tunnel syndrome and ATTR amyloid in surrounding adipose and vascular tissue indicate that amyloid deposits in ligamentum flavum may be an early manifestation of systemic ATTR disease.

    Download full text (pdf)
    fulltext
  • 19.
    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)
  • 20.
    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.

  • 21.
    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.

  • 22.
    Espes, Daniel
    et al.
    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.
    [Amyloid from insulin treatment: a pitfall for the pathologist and the diabetologist]2020In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 117, article id FSUFArticle in journal (Refereed)
    Abstract [sv]

    Biopsies from six diabetic patients with subcutaneous amyloid deposits formed by injected insulin have been sent to our laboratory during the last year. In all but one of the six patients a subcutaneous adipose tissue biopsy was taken due to suspicion of systemic amyloidosis. Four of these patients had renal insufficiency, with monoclonal gammopathy of undetermined significance (MGUS) in three while the fifth had heredity for transthyretin amyloidosis. In the sixth patient a biopsy was taken due to subcutaneous nodules at insulin injection sites. In all biopsies, large amounts of amyloid were present and their biochemical nature was elucidated by immunohistochemistry or western blot. The risk of incorrect interpretation with misdiagnosis of systemic amyloidosis is underlined. The consequences this may have on insulin treatment are insufficiently studied.

  • 23.
    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, 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.

    Download full text (pdf)
    fulltext
  • 24.
    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.

  • 25. 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.

  • 26.
    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)
  • 27.
    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.

  • 28. 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)
  • 29.
    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.

    Download full text (pdf)
    FULLTEXT01
  • 30. 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.

  • 31.
    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.

  • 32.
    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.

    Download full text (pdf)
    fulltext
  • 33. 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)
  • 34.
    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.

  • 35.
    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.

  • 36.
    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.

  • 37.
    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.

  • 38.
    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, 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.

  • 39. 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.

  • 40.
    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.

  • 41.
    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.

  • 42.
    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.

  • 43.
    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.

  • 44.
    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, 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.

    Download full text (pdf)
    FULLTEXT01
  • 45. Linke, Reinhold P
    et al.
    Joswig, Reinhild
    Murphy, Charles L
    Wang, Shuching
    Zhou, Hui
    Gross, Ulrich
    Rocken, Christoph
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Weiss, Deborah T
    Solomon, Alan
    Senile seminal vesicle amyloid is derived from semenogelin I.2005In: Journal of Laboratory and Clinical Medicine, ISSN 0022-2143, E-ISSN 1532-6543, Vol. 145, no 4, p. 187-93Article in journal (Refereed)
  • 46. 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)
  • 47. 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.

  • 48.
    Milardi, Danilo
    et al.
    CNR, Ist Cristallog, I-95126 Catania, Italy.
    Gazit, Ehud
    Tel Aviv Univ, Dept Mol Microbiol & Biotechnol, Shmunis Sch Biomed & Canc Res, George S Wise Fac Life Sci, IL-6997801 Tel Aviv, Israel.
    Radford, Sheena E.
    Univ Leeds, Astbury Ctr Struct Mol Biol, Sch Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England.
    Xu, Yong
    Univ Leeds, Astbury Ctr Struct Mol Biol, Sch Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England.
    Gallardo, Rodrigo U.
    Univ Leeds, Astbury Ctr Struct Mol Biol, Sch Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England.
    Caflisch, Amedeo
    Univ Zurich, Dept Biochem, CH-8057 Zurich, Switzerland.
    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.
    La Rosa, Carmelo
    Univ Catania, Dipartimento Sci Chim, I-95125 Catania, Italy.
    Ramamoorthy, Ayyalusamy
    Univ Michigan, Dept Chem Biomed Engn Macromol Sci & Engn, Biophys, Ann Arbor, MI 41809 USA.
    Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes2021In: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 121, no 3, p. 1845-1893Article, review/survey (Refereed)
    Abstract [en]

    The possible link between hIAPP accumulation and β-cell death in diabetic patients has inspired numerous studies focusing on amyloid structures and aggregation pathways of this hormone. Recent studies have reported on the importance of early oligomeric intermediates, the many roles of their interactions with lipid membrane, pH, insulin, and zinc on the mechanism of aggregation of hIAPP. The challenges posed by the transient nature of amyloid oligomers, their structural heterogeneity, and the complex nature of their interaction with lipid membranes have resulted in the development of a wide range of biophysical and chemical approaches to characterize the aggregation process. While the cellular processes and factors activating hIAPP-mediated cytotoxicity are still not clear, it has recently been suggested that its impaired turnover and cellular processing by proteasome and autophagy may contribute significantly toward toxic hIAPP accumulation and, eventually, β-cell death. Therefore, studies focusing on the restoration of hIAPP proteostasis may represent a promising arena for the design of effective therapies. In this review we discuss the current knowledge of the structures and pathology associated with hIAPP self-assembly and point out the opportunities for therapy that a detailed biochemical, biophysical, and cellular understanding of its aggregation may unveil.

  • 49.
    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.

  • 50.
    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)
123 1 - 50 of 124
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf