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  • 101.
    Nordeman, Patrik
    et al.
    Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
    Johansson, Leif B. G.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Estrada, Sergio
    Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden..
    Hall, Håkan
    Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden..
    Sjölander, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Westermark, Gunilla T.
    Department of Medicinal Cell Biology, Uppsala University, Uppsala, Sweden.
    Westermark, Per
    Department of Immunology, Genetics and Pathology, Uppsala University, UppsalaSweden.
    Nilsson, Lars
    Department of Pharmacology, University of Oslo, Oslo, Norway.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, K. Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Antoni, Gunnar
    Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
    11C and 18FRadiolabeling of Tetra- and Pentathiophenes as PET-ligands for Amyloid Protein Aggregates2016In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 7, no 4, p. 368-373Article in journal (Refereed)
    Abstract [en]

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

  • 102.
    Novotny, Renata
    et al.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany; University of Tubingen, Germany.
    Langer, Franziska
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Mahler, Jasmin
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany; University of Tubingen, Germany.
    Skodras, Angelos
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Vlachos, Andreas
    Goethe University of Frankfurt, Germany.
    Wegenast-Braun, Bettina M.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Kaeser, Stephan A.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Neher, Jonas J.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Eisele, Yvonne S.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Pietrowski, Marie J.
    University of Freiburg, Germany.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Deller, Thomas
    Goethe University of Frankfurt, Germany.
    Staufenbiel, Matthias
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Heimrich, Bernd
    University of Freiburg, Germany.
    Jucker, Mathias
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Conversion of Synthetic A beta to In Vivo Active Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model2016In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 36, no 18, p. 5084-5093Article in journal (Refereed)
    Abstract [en]

    The aggregation of amyloid-beta peptide (A beta) inbrain is an early event and hallmark of Alzheimers disease (AD). We combined the advantages of in vitro and in vivo approaches to study cerebral beta-amyloidosis by establishing a long-term hippocampal slice culture(HSC) model. While no A beta deposition was noted in untreated HSCs of postnatal A beta precursor protein transgenic (APP tg) mice, A beta deposition emerged in HSCs when cultures were treated once with brain extract from aged APP tg mice and the culture medium was continuously supplemented with synthetic A beta. Seeded A beta deposition was also observed under the same conditions in HSCs derived from wild-type or App-null mice but in no comparable way when HSCs were fixed before cultivation. Both the nature of the brain extract and the synthetic A beta species determined the conformational characteristics of HSCA beta deposition. HSCA beta deposits induced a microglia response, spine loss, and neuritic dystrophy but no obvious neuron loss. Remarkably, in contrast to in vitro aggregated synthetic A beta, homogenates of A beta deposits containing HSCs induced cerebral beta-amyloidosis upon intracerebral inoculation into young APP tg mice. Our results demonstrate that a living cellular environment promotes the seeded conversion of synthetic A beta into a potent in vivo seeding-active form.

  • 103.
    Nystrom, Sofie
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nelson, Erin
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Reitan, Nina
    Norwegian University of Science and Technology.
    Ellingsen, Pal
    Norwegian University of Science and Technology.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Mason, Jeffrey
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Johansson, Leif
    Linköping University, Department of Physics, Chemistry and Biology, Semiconductor Materials. Linköping University, The Institute of Technology.
    Sluzny, Chanan
    Appl Spectral Imaging, Migdal Haemeq.
    Handrick, Susann
    Charite.
    Prokop, Stefan
    Charite.
    Wegenast-Braun, Bettina
    German Centre Neurodegenerat Disease.
    Hornemann, Simone
    University of Zurich Hospital.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Lindgren, Mikael
    Norwegian University of Science and Technology.
    Heppner, Frank
    Charite.
    Jucker, Mathias
    German Centre Neurodegenerat Disease.
    Aguzzi, Adriano
    University of Zurich Hospital.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Monitoring amyloid formation and maturation in vitro and in vivo using LCO fluorescence in PRION, vol 6, issue , pp 13-132012In: PRION, Landes Bioscience , 2012, Vol. 6, p. 13-13Conference paper (Refereed)
    Abstract [en]

    n/a

  • 104.
    Nyström, Sofie
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Imaging Amyloid Tissues Stained with Luminescent Conjugated Oligothiophenes by Hyperspectral Confocal Microscopy and Fluorescence Lifetime Imaging2017In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 128, article id e56279Article in journal (Refereed)
    Abstract [en]

    Proteins that deposit as amyloid in tissues throughout the body can be the cause or consequence of a large number of diseases. Among these we find neurodegenerative diseases such as Alzheimers and Parkinsons disease afflicting primarily the central nervous system, and systemic amyloidosis where serum amyloid A, transthyretin and IgG light chains deposit as amyloid in liver, carpal tunnel, spleen, kidney, heart, and other peripheral tissues. Amyloid has been known and studied for more than a century, often using amyloid specific dyes such as Congo red and Thioflavin T (ThT) or Thioflavin (ThS). In this paper, we present heptamer-formyl thiophene acetic acid (hFTAA) as an example of recently developed complements to these dyes called luminescent conjugated oligothiophenes (LCOs). hFTAA is easy to use and is compatible with co-staining in immunofluorescence or with other cellular markers. Extensive research has proven that hFTAA detects a wider range of disease associated protein aggregates than conventional amyloid dyes. In addition, hFTAA can also be applied for optical assignment of distinct aggregated morphotypes to allow studies of amyloid fibril polymorphism. While the imaging methodology applied is optional, we here demonstrate hyperspectral imaging (HIS), laser scanning confocal microscopy and fluorescence lifetime imaging (FLIM). These examples show some of the imaging techniques where LCOs can be used as tools to gain more detailed knowledge of the formation and structural properties of amyloids. An important limitation to the technique is, as for all conventional optical microscopy techniques, the requirement for microscopic size of aggregates to allow detection. Furthermore, the aggregate should comprise a repetitive beta-sheet structure to allow for hFTAA binding. Excessive fixation and/or epitope exposure that modify the aggregate structure or conformation can render poor hFTAA binding and hence pose limitations to accurate imaging.

  • 105.
    Nyström, Sofie
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Multiple substitutions of methionine 129 in human prion protein reveal its importance in the amyloid fibrillation pathway2012In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 31, p. 25975-25984Article in journal (Refereed)
    Abstract [en]

    The role of the polymorphism Met or Val in position 129 in the human prion protein is well documented regarding disease susceptibility and clinical manifestations. However, little is known about the molecular background to this phenomenon. We investigated herein the conformational stability, amyloid fibrillation kinetics, and seeding propensity of different 129 mutants, located in β-strand 1 of PrP (Met129 (WT), M129A, M129V, M129L, M129W, M129P, M129E, M129K, and M129C) in HuPrP(90–231). The mutations M129V, M129L, M129K, and M129C did not affect stability (midpoints of thermal denaturation, Tm = 65–66 °C), whereas the mutants M129A and M129E and the largest side chain M129W were destabilized by 3–4 °C. The most destabilizing substitution was M129P, which lowered the Tm by 7.2 °C. All mutants, except for M129C, formed amyloid-like fibrils within hours during fibril formation under near physiological conditions. Fibril-forming mutants showed a sigmoidal kinetic profile and showed shorter lag times during seeding with preformed amyloid fibrils implicating a nucleated polymerization reaction. In the spontaneous reactions, the lag time of fibril formation was rather uniform for the mutants M129A, M129V, and M129L resembling the wild type. When the substituted amino acid had a distinct feature discriminating it from the wild type, such as size (M129W), charge (M129E, M129K), or rotational constraint (M129P), the fibrillation was impeded. M129C did not form ThT/Congo red-positive fibrils, and non-reducing SDS-PAGE of M129C during fibrillation conditions at different time points revealed covalent dimer formation already 15 min after fibrillation reaction initiation. Position 129 appears to be a key site for dictating PrP receptiveness toward recruitment into the amyloid state.

  • 106.
    Nyström, Sofie
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Propagating Artificial Amyloid Strains of Recombinant Human Prion Protein with Mutations in Position 1292010In: Prion, ISSN 1933-6896, E-ISSN 1933-690X, Vol. 4, no 3, p. 124-124Article in journal (Other academic)
    Abstract [en]

    The influence of the polymorphism M129V in the human PrPgene is well documented. Most cases of sporadic CJD afflicthomozygous individuals. Differences in codon 129 genotypegive rise to differences in phenotype regarding plaque and clinicalsymptoms. Despite this, little is known about the molecularbackground to this phenomenon.

    To study this phenomenon in greater detail we employedrecombinant human prion protein. Using several artificial mutationsallowed us to study the influence of different amino acidproperties on the formation of amyloid prion protein. The variantsused were 129A, 129V, 129L, 129M, 129W, 129P, 129E and129K. Three mutants were chosen to vary the hydrophobicity,the tryptophan mutant was chosen due to its bulkiness and theproline for its constraint of the polypeptide backbone. 129E and129K may give information regarding the effect of charge in this position.

    The protein was expressed in Escherichia coli, purified andsubjected to agitation at 37°C at physiological pH and salt concentration(Almstedt et al. Prion 2009). All mutants formedcongophilic and Thioflavine T positive aggregates within hours.Fibrillar morphology was also confirmed using transmission electronmicroscopy.

    Seeding the mutant proteins with preformed fibrils of themutant itself or of wild type protein revealed differences in seedingefficiency for the different mutants. By monitoring the fibrilsresulting from the seeded fibrillation reactions using luminescentconjugated polymers, a templating effect was seen. This strainlikebehavior was followed through several generations of fibrils.The fragility of the seeding fibrils was taken under considerationand was analyzed using urea denaturation.

    Almstedt, Nyström S, Nilsson P, Hammarström P. Prion2009; 3:224-35.

  • 107.
    Nyström, Sofie
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Psonka-Antonczyk, Katarzyna M.
    Norwegian University of Science and Technology, Norway .
    Ellingsen, Pal Gunnar
    Norwegian University of Science and Technology, Norway .
    Johansson, Leif
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Reitan, Nina
    Norwegian University of Science and Technology, Norway .
    Handrick, Susann
    University of Medical Berlin, Germany .
    Prokop, Stefan
    University of Medical Berlin, Germany .
    Heppner, Frank L.
    University of Medical Berlin, Germany .
    Wegenast-Braun, Bettina M.
    German Centre Neurodegenerat Disease, Germany .
    Jucker, Mathias
    German Centre Neurodegenerat Disease, Germany .
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Torger Stokke, Bjorn
    Norwegian University of Science and Technology, Norway .
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter K R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Evidence for Age-Dependent in Vivo Conformational Rearrangement within A beta Amyloid Deposits2013In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 8, no 6, p. 1128-1133Article in journal (Refereed)
    Abstract [en]

    Deposition of aggregated A beta peptide in the brain is one of the major hallmarks of Alzheimers disease. Using a combination of two structurally different, but related, hypersensitive fluorescent amyloid markers, LCOs, reporting on separate ultrastructural elements, we show that conformational rearrangement occurs within A beta plaques of transgenic mouse models as the animals age. This important mechanistic insight should aid the design and evaluation of experiments currently using plaque load as readout.

  • 108.
    Nyström, Sofie
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Vahdat Shariat Panahi, Aida
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Westermark, Per
    d Department of Immunology , Genetics and Pathology, Uppsala University , Uppsala , Sweden.
    Westermark, Gunilla T.
    e Department of Medical Cell Biology , Uppsala University , Uppsala , Sweden.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lundmark, Katarzyna
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Seed-dependent templating of murine AA amyloidosis2017In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, no sup1, p. 140-141Article in journal (Other academic)
    Abstract [en]

    n/a

  • 109.
    Ostapchenko, Valeriy G
    et al.
    Universityof Maryland.
    Sawaya, Michael R
    University of California Los Angeles.
    Makarava, Natallia
    University of Maryland.
    Savtchenko, Regina
    University of Maryland.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Eisenberg, David
    University of California Los Angeles.
    Baskakov, Ilia V
    University of Maryland.
    Two Amyloid States of the Prion Protein Display Significantly Different Folding Patterns2010In: JOURNAL OF MOLECULAR BIOLOGY, ISSN 0022-2836, Vol. 400, no 4, p. 908-921Article in journal (Refereed)
    Abstract [en]

    It has been well established that a single amino acid sequence can give rise to several conformationally distinct amyloid states. The extent to which amyloid structures formed within the same sequence are different, however, remains unclear. To address this question, we studied two amyloid states (referred to as R- and S-fibrils) produced in vitro from highly purified full-length recombinant prion protein. Several biophysical techniques including X-ray diffraction, CD, Fourier transform infrared spectroscopy (FTIR), hydrogen-deuterium exchange, proteinase K digestion, and binding of a conformation-sensitive fluorescence dye revealed that R- and S-fibrils have substantially different secondary, tertiary, and quaternary structures. While both states displayed a 4. 8-angstrom meridional X-ray diffraction typical for amyloid cross-beta-spines, they showed markedly different equatorial profiles, suggesting different folding pattern of beta-strands. The experiments on hydrogen-deuterium exchange monitored by FTIR revealed that only small fractions of amide protons were protected in R- or S-fibrils, an argument for the dynamic nature of their cross-beta-structure. Despite this fact, both amyloid states were found to be very stable conformationally as judged from temperature-induced denaturation monitored by FTIR and the conformation-sensitive dye. Upon heating to 80 degrees C, only local unfolding was revealed, while individual state-specific cross-beta features were preserved. The current studies demonstrated that the two amyloid states formed by the same amino acid sequence exhibited significantly different folding patterns that presumably reflect two different architectures of cross-beta-structure. Both Sand R-fibrils, however, shared high conformational stability, arguing that the energy landscape for protein folding and aggregation can contain several deep free-energy minima.

  • 110.
    Philipson, O.
    et al.
    Uppsala University.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Portelius, E.
    Sahlgrenska University Hospital.
    Olofsson, T.
    Uppsala University.
    Ingelsson, M.
    Uppsala University.
    Hyman, B.T.
    Massachusetts General Hospital.
    Blennow, K.
    Sahlgrenska University Hospital.
    Lannfelt, L.
    Uppsala University.
    Kalimo, H.
    Uppsala University.
    Nilsson, L.N.G.
    Uppsala University.
    A highly insoluble state of Aβ similar to that of Alzheimers disease brain is found in Arctic APP transgenic mice2009In: Neurobiology of Aging, ISSN 0197-4580, Vol. 30, no 9, p. 1393-1405Article in journal (Refereed)
    Abstract [en]

    Amyloid-β (Aβ) is a major drug target in Alzheimers disease. Here, we demonstrate that deposited Aβ is SDS insoluble in tgAPP-ArcSwe, a transgenic mouse model harboring the Arctic (E693G) and Swedish (KM670/671NL) APP mutations. Formic acid was needed to extract the majority of deposited Aβ in both tgAPP-ArcSwe and Alzheimers disease brain, but not in a commonly used type of mouse model with the Swedish mutation alone. Interestingly, the insoluble state of Arctic Aβ was determined early on and did not gradually evolve with time. In tgAPP-ArcSwe, Aβ plaques displayed a patchy morphology with bundles of Aβ fibrils, whereas amyloid cores in tgAPP-Swe were circular with radiating fibrils. Amyloid was more densely stacked in tgAPP-ArcSwe, as demonstrated with a conformation sensitive probe. A reduced increase in plasma Aβ was observed following acute administration of an Aβ antibody in tgAPP-ArcSwe, results that might imply reduced brain to plasma Aβ efflux. TgAPP-ArcSwe, with its insoluble state of deposited Aβ, could serve as a complementary model to better predict the outcome of clinical trials.

  • 111.
    Psonka-Antonczyk, Katarzyna M.
    et al.
    Department of Physics, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Johansson, Leif
    Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Chemistry.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Department of Physics, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
    Stokke, Björn T.
    Department of Physics, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nanoscale Structure and Spectroscopic Probing of A beta 1-40 Fibril Bundle Formation2016In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 4, article id 44Article in journal (Refereed)
    Abstract [en]

    Amyloid plaques composed of fibrillar Amyloid-beta (A beta) are hallmarks of Alzheimers disease. However, A beta fibrils are morphologically heterogeneous. Conformation sensitive luminescent conjugated oligothiophenes (LCOs) are versatile tools for monitoring such fibril polymorphism in vivo and in vitro. Biophysical methods applied on in vitro generated A beta fibrils, stained with LCOs with different binding and fluorescence properties, can be used to characterize the A beta fibrillation in depth, far beyond that possible for in vivo generated amyloid plaques. In this study, in vitro fibrillation of the A beta 1-40 peptide was monitored by time-lapse transmission electron microscopy, LCO fluorescence, and atomic force microscopy. Differences in the LCO binding in combination with nanoscale imaging revealed that spectral variation correlated with fibrils transforming from solitary filaments (empty set similar to 2.5 nm) into higher order bundled structures (empty set similar to 5 nm). These detailed in vitro experiments can be used to derive data that reflects the heterogeneity of in vivo generated A beta plaques observed by LCO fluorescence. Our work provides new structural basis for targeted drug design and molecular probe development for amyloid imaging.

  • 112.
    Rasmussen, Jay
    et al.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany; University of Tubingen, Germany.
    Mahler, Jasmin
    University of Tubingen, Germany.
    Beschorner, Natalie
    University of Tubingen, Germany.
    Kaeser, Stephan A.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Haesler, Lisa M.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Baumann, Frank
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Portelius, Erik
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Blennow, Kaj
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Lashley, Tammaryn
    UCL, England.
    Fox, Nick C.
    UCL, England.
    Sepulveda-Falla, Diego
    University of Medical Centre Hamburg Eppendorf, Germany; University of Antioquia, Colombia; University of Antioquia, Colombia.
    Glatzel, Markus
    University of Medical Centre Hamburg Eppendorf, Germany.
    Oblak, Adrian L.
    Indiana University of School Med, IN 46202 USA.
    Ghetti, Bernardino
    Indiana University of School Med, IN 46202 USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Staufenbiel, Matthias
    University of Tubingen, Germany.
    Walker, Lary C.
    Emory University, GA 30329 USA.
    Jucker, Mathias
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimers disease2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 49, p. 13018-13023Article in journal (Refereed)
    Abstract [en]

    The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-beta peptide (A beta) has been shown to adopt distinct structural conformations with different biological activities, we asked whether A beta can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of beta-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimers disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of A beta nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to A beta plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic A beta-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic A beta among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between A beta conformation and clinical phenotype.

  • 113.
    Ries, Jonas
    et al.
    EMBL Heidelberg, Germany .
    Udayar, Vinod
    University of Zurich, Switzerland .
    Soragni, Alice
    ETH, Switzerland .
    Hornemann, Simone
    University of Zurich, Switzerland .
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Riek, Roland
    ETH, Switzerland .
    Hock, Christoph
    University of Zurich, Switzerland .
    Ewers, Helge
    ETH, Switzerland .
    Aguzzi, Adriano A.
    University of Zurich, Switzerland .
    Rajendran, Lawrence
    University of Zurich, Switzerland .
    Superresolution Imaging of Amyloid Fibrils with Binding-Activated Probes2013In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 4, no 7, p. 1057-1061Article in journal (Refereed)
    Abstract [en]

    Protein misfolding into amyloid-like aggregates underlies many neurodegenerative diseases. Thus, insights into the structure and function of these amyloids will provide valuable information on the pathological mechanisms involved and aid in the design of improved drugs for treating amyloid-based disorders. However, determining the structure of endogenous amyloids at high resolution has been difficult. Here we employ binding-activated localization microscopy (BALM) to acquire superresolution images of alpha-synuclein amyloid fibrils with unprecedented optical resolution. We propose that BALM imaging can be extended to study the structure of other amyloids, for differential diagnosis of amyloid-related diseases and for discovery of drugs that perturb amyloid structure for therapy.

  • 114.
    Rouhbakhsh, Zeinab
    et al.
    Not Found:Linkoping Univ, Dept Phys Chem and Biol, Div Mol Phys, Lab Mol Mat, S-58183 Linkoping, Sweden; Linkoping Univ, Dept Phys, Div Chem, Chem and Biol, S-58183 Linkoping, Sweden.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Martinsson, Erik
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Svärd, Anna
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Back, Marcus
    Ferdowsi Univ Mashhad, Iran.
    Housaindokht, Mohammad R.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Ferdowsi Univ Mashhad, Iran.
    Selegård, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Self-Assembly of a Structurally Defined Chiro-Optical Peptide-Oligothiophene Hybrid Material2018In: ACS OMEGA, ISSN 2470-1343, Vol. 3, no 11, p. 15066-15075Article in journal (Refereed)
    Abstract [en]

    Conducting polymers are routinely used in optoelectronic biomaterials, but large polymer polydispersity and poor aqueous compatibility complicate integration with biomolecular templates and development of discrete and defined supramolecular complexes. Herein, we report on a chiro-optical hybrid material generated by the self-assembly of an anionic peptide and a chemically defined cationic pentameric thiophene in aqueous environment. The peptide acts as a stereochemical template for the thiophene and adopts an a-helical conformation upon association, inducing optical activity in the thiophene r-n * transition region. Theoretical calculations confirm the experimentally observed induced structural changes and indicate the importance of electrostatic interactions in the complex. The association process is also probed at the substrate-solvent interface using peptide-functionalized gold nanoparticles, indicating that the peptide can also act as a scaffold when immobilized, resulting in structurally well-defined supramolecular complexes. The hybrid complex could rapidly be assembled, and the kinetics of the formation could be monitored by utilizing the local surface plasmon resonance originating from the gold nanoparticles. We foresee that these findings will aid in designing novel hybrid materials and provide a possible route for the development of functional optoelectronic interfaces for both biomaterials and energy harvesting applications.

  • 115.
    Schuetz, Anne K.
    et al.
    Swiss Fed Inst Technol, Switzerland.
    Hornemann, Simone
    Univ Zurich, Switzerland.
    Waelti, Marielle A.
    Swiss Fed Inst Technol, Switzerland.
    Greuter, Ladina
    Univ Zurich, Switzerland.
    Tiberi, Cinzia
    Univ Zurich, Switzerland.
    Cadalbert, Riccardo
    Swiss Fed Inst Technol, Switzerland.
    Gantner, Matthias
    Swiss Fed Inst Technol, Switzerland.
    Riek, Roland
    Swiss Fed Inst Technol, Switzerland.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Boeckmann, Anja
    Univ Lyon 1, France.
    Aguzzi, Adriano
    Univ Zurich, Switzerland.
    Meier, Beat H.
    Swiss Fed Inst Technol, Switzerland.
    Binding of Polythiophenes to Amyloids: Structural Mapping of the Pharmacophore2018In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 9, no 3, p. 475-481Article in journal (Refereed)
    Abstract [en]

    Luminescent conjugated polythiophenes bind to amyloid proteins with high affinity. Their fluorescence properties, which are modulated by the detailed conformation in the bound state, are highly sensitive to structural features of the amyloid. Polythiophenes therefore represent diagnostic markers for the detection and differentiation of pathological amyloid aggregates. 560 We clarify the binding site and mode of two different polythiophenes to fibrils of the prion domain of the HET-s protein by solid-state NMR and correlate these findings with their fluorescence properties. We demonstrate how amyloid dyes recognize distinct binding sites with specific topological features. Regularly spaced surface charge patterns and well-accessible grooves on the fibril surface define the pharmacophore of the amyloid, which in turn determines the binding mode and fluorescence wavelength of the polythiophene.

  • 116.
    Schultz, Sebastian
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Fly model of type 2 diabetes: processing of proIAPP makes a difference2010In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 17, no S1, p. 44-45Article in journal (Other academic)
    Abstract [en]

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

  • 117.
    Schultz, Sebastian
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Torstensdotter Westermark, Gunilla
    Uppsala University.
    Drosophila Melanogaster as a Model System for Studies of Islet Amyloid Polypeptide Aggregation2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6Article in journal (Refereed)
    Abstract [en]

    Background: Recent research supports that aggregation of islet amyloid polypeptide (IAPP) leads to cell death and this makes islet amyloid a plausible cause for the reduction of beta cell mass, demonstrated in patients with type 2 diabetes. IAPP is produced by the beta cells as a prohormone, and proIAPP is processed into IAPP by the prohormone convertases PC1/3 and PC2 in the secretory granules. Little is known about the pathogenesis for islet amyloid and which intracellular mechanisms are involved in amyloidogenesis and induction of cell death.

    Methodology/Principal Findings: We have established expression of human proIAPP (hproIAPP), human IAPP (hIAPP) and the non-amyloidogenic mouse IAPP (mIAPP) in Drosophila melanogaster, and compared survival of flies with the expression driven to different cell populations. Only flies expressing hproIAPP in neurons driven by the Gal4 driver elavC(155,Gal4) showed a reduction in lifespan whereas neither expression of hIAPP or mIAPP influenced survival. Both hIAPP and hproIAPP expression caused formation of aggregates in CNS and fat body region, and these aggregates were both stained by the dyes Congo red and pFTAA, both known to detect amyloid. Also, the morphology of the highly organized protein granules that developed in the fat body of the head in hIAPP and hproIAPP expressing flies was characterized, and determined to consist of 15.8 nm thick pentagonal rod-like structures.

    Conclusions/Significance: These findings point to a potential for Drosophila melanogaster to serve as a model system for studies of hproIAPP and hIAPP expression with subsequent aggregation and developed pathology.

  • 118.
    Sekijima, Yoshiki
    et al.
    Shinshu University,Matsumoto, Japan.
    Campos, Raul Ivan
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Yoshinaga, Tsuneaki
    Shinshu University, Matsumoto, Japan.
    Nagamatsu, Kiyoshiro
    Shinshu University, Matsumoto, Japan.
    Yazaki, Masahide
    Shinshu University,Matsumoto, Japan.
    Kametani, Fuyuki
    Tokyo Metropolitan Org Medical Research, Japan.
    Ikeda, Shu-ichi
    Shinshu University, Matsumoto, Japan.
    Pathological, biochemical, and biophysical characteristics of the transthyretin variant Y114H (p.Y134H) explain its very mild clinical phenotype2015In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 20, no 4, p. 372-379Article in journal (Refereed)
    Abstract [en]

    Transthyretin (TTR) is a homotetrameric protein that must misfold in order to form amyloid fibrils. Misfolding includes rate limiting tetramer dissociation, followed by fast tertiary structural changes of the monomer that enable aggregation. Hereditary ATTR amyloidosis is an autosomal dominant genetic disorder with systemic deposition of amyloid fibrils induced by TTR gene mutation. We identified a rare Y114H (p.Y134H) TTR variant in a Japanese patient presenting with late-onset, very mild clinical course. The patient had an extremely low serum variant TTR concentration (18% of total TTR), whereas the composition of variant TTR was 55% in amyloid fibrils in tenosynovial tissues obtained at carpal tunnel release surgery. The amyloid fibril deposits in the ATTR Y114H patient had an altered structure compared with that in wild-type ATTR patients, as determined by luminescent conjugated poly/oligo-thiophene fluorescence spectroscopy. Biophysical studies using recombinant protein showed that Y114H TTR was markedly destabilized both thermodynamically and kinetically and was highly amyloidogenic in vitro. These data suggest that extremely low serum variant Y114H TTR concentration, probably due to endoplasmic reticulum-associated degradation of unstable variant TTR protein, protected this patient from severe amyloidosis, as self-assembly of the amyloidogenic intermediate is a concentration-dependent process.

  • 119.
    Selegård, Robert
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Rouhbalchsh, Zeinab
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Johansson, Leif
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Norman, Patrick
    KTH Royal Institute Technology, Sweden.
    Linares, Mathieu
    KTH Royal Institute Technology, Sweden.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Distinct Electrostatic Interactions Govern the Chiro-Optical Properties and Architectural Arrangement of Peptide-Oligothiophene Hybrid Materials2017In: Macromolecules, ISSN 0024-9297, E-ISSN 1520-5835, Vol. 50, no 18, p. 7102-7110Article in journal (Refereed)
    Abstract [en]

    The development of chiral optoelectronic materials is of great interest due to their potential of being utilized in electronic devices, biosensors, and artificial enzymes. Herein, we report the chiral optical properties and architectural arrangement of optoelectronic materials generated from noncovalent self-assembly of a cationic synthetic peptide and five chemically defined anionic pentameric oligothiophenes. The peptide-oligothiophene hybrid materials exhibit a three-dimensional ordered helical structure and optical activity in the pi-pi* transition region that are observed due to a single chain induced chirality of the conjugated thiophene backbone upon interaction with the peptide. The latter property is highly dependent on electrostatic interactions between the peptide and the oligothiophene, verifying that a distinct spacing of the carboxyl groups along the thiophene backbone is a major chemical determinant for having a hybrid material with distinct optoelectronic properties. The necessity of the electrostatic interaction between specific carboxyl functionalities along the thiophene backbone and the lysine residues of the peptide, as well as the induced circular dichroism of the thiophene backbone, was also confirmed by theoretical calculations. We foresee that our findings will aid in designing optoelectronic materials with dynamic architectonical precisions as well as offer the possibility to create the next generation of materials for organic electronics and organic bioelectronics.

  • 120.
    Shirani, Hamid
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Appelqvist, Hanna
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Cairns, Nigel J.
    Washington University, MO USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Synthesis of Thiophene-Based Optical Ligands That Selectively Detect Tau Pathology in Alzheimers Disease2017In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, no 67, p. 17127-17135Article in journal (Refereed)
    Abstract [en]

    The accumulation of protein aggregates is associated with many devastating neurodegenerative diseases and the development of molecular ligands able to detect these pathological hallmarks is essential. Here, the synthesis of thiophene based optical ligands, denoted bi-thiophene-vinyl-benzothiazoles (bTVBTs) that can be utilized for selective assignment of tau aggregates in brain tissue with Alzheimers disease (AD) pathology is reported. The ability of the ligands to selectively distinguish tau deposits from the other AD associated pathological hallmark, senile plaques consisting of aggregated amyloid- (A) peptide, was reduced when the chemical composition of the ligands was altered, verifying that specific molecular interactions between the ligands and the aggregates are necessary for the selective detection of tau deposits. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between aggregated proteinaceous species consisting of different proteins. In addition, the bTVBT scaffold might be utilized to create powerful practical research tools for studying the underlying molecular events of tau aggregation and for creating novel agents for clinical imaging of tau pathology in AD.

  • 121.
    Shirani, Hamid
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Linares, Mathieu
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Chemistry. Linköping University, Faculty of Science & Engineering.
    Sigurdson, Christina J.
    University of Calif San Diego, CA 92093 USA.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Norman, Patrick
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    A Palette of Fluorescent Thiophene-Based Ligands for the Identification of Protein Aggregates2015In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 43, p. 15133-15137Article in journal (Refereed)
    Abstract [en]

    By replacing the central thiophene unit of an anionic pentameric oligothiophene with other heterocyclic moities, a palette of pentameric thiophene-based ligands with distinct fluorescent properties were synthesized. All ligands displayed superior selectivity towards recombinant amyloid fibrils as well as disease-associated protein aggregates in tissue sections.

  • 122.
    Sigurdson, Christina J.
    et al.
    University of California San Diego.
    Bartz, Jason C.
    Creighton University.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Tracking protein aggregate interactions2011In: PRION, ISSN 1933-6896, Vol. 5, no 2, p. 52-55Article in journal (Refereed)
    Abstract [en]

    Amyloid fibrils share a structural motif consisting of highly ordered beta-sheets aligned perpendicular to the fibril axis.(1,2) At each fibril end, beta-sheets provide a template for recruiting and converting monomers.(3) Different amyloid fibrils often co-occur in the same individual, yet whether a protein aggregate aids or inhibits the assembly of a heterologous protein is unclear. In prion disease, diverse prion aggregate structures, known as strains, are thought to be the basis of disparate disease phenotypes in the same species expressing identical prion protein sequences.(4-7) Here we explore the interactions reported to occur when two distinct prion strains occur together in the central nervous system.

  • 123.
    Sigurdson, Christina J
    et al.
    University of California San Diego.
    Joshi-Barr, Shivanjali
    University of California San Diego.
    Bett, Cyrus
    University of California San Diego.
    Winson, Olivia
    University of California San Diego.
    Manco, Giuseppe
    University of Vet Medical Vienna.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Margalith, Ilan
    Prionics AG.
    Peretz, David
    University of California San Diego.
    Hornemann, Simone
    Swiss Federal Institute of Technology.
    Wuethrich, Kurt
    Scripps Research Institute.
    Aguzzi, Adriano
    University of Spital Zurich.
    Spongiform Encephalopathy in Transgenic Mice Expressing a Point Mutation in the beta 2-alpha 2 Loop of the Prion Protein2011In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 39, p. 13840-13847Article in journal (Refereed)
    Abstract [en]

    Transmissible spongiform encephalopathies are fatal neurodegenerative diseases attributed to misfolding of the cellular prion protein, PrP(C), into a beta-sheet-rich, aggregated isoform, PrP(Sc). We previously found that expression of mouse PrP with the two amino acid substitutions S170N and N174T, which result in high structural order of the beta 2-alpha 2 loop in the NMR structure at pH 4.5 and 20 C, caused transmissible de novo prion disease in transgenic mice. Here we report that expression of mouse PrP with the single-residue substitution D167S, which also results in a structurally well ordered beta 2-alpha 2 loop at 20 degrees C, elicits spontaneous PrP aggregation in vivo. Transgenic mice expressing PrP(D167S) developed a progressive encephalopathy characterized by abundant PrP plaque formation, spongiform change, and gliosis. These results add to the evidence that the beta 2-alpha 2 loop has an important role in intermolecular interactions, including that it may be a key determinant of prion protein aggregation.

  • 124.
    Sigurdson, Christina J
    et al.
    UniversitätsSpital Zürich.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Hornemann, Simone
    Institut für Molekularbiologie und Biophysik, ETH Zürich.
    Heikenwalder, Mathias
    UniversitätsSpital Zürich.
    Manco, Giuseppe
    UniversitätsSpital Zürich.
    Schwarz, Petra
    UniversitätsSpital Zürich.
    Ott, David
    UniversitätsSpital Zürich.
    Rülicke, Thomas
    University of Veterinary Medicine Vienna.
    Liberski, Pawel P
    Medical University Lodz.
    Julius, Christian
    UniversitätsSpital Zürich.
    Falsig, Jeppe
    UniversitätsSpital Zürich.
    Stitz, Lothar
    ETH Zürich.
    Wüthrich, Kurt
    Institut für Molekularbiologie und Biophysik, ETH Zürich.
    Aguzzi, Adriano
    UniversitätsSpital Zürich.
    De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis.2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 1, p. 304-309Article in journal (Refereed)
    Abstract [en]

    Most transmissible spongiform encephalopathies arise either spontaneously or by infection. Mutations of PRNP, which encodes the prion protein, PrP, segregate with phenotypically similar diseases. Here we report that moderate overexpression in transgenic mice of mPrP(170N,174T), a mouse PrP with two point mutations that subtly affect the structure of its globular domain, causes a fully penetrant lethal spongiform encephalopathy with cerebral PrP plaques. This genetic disease was reproduced with 100% attack rate by intracerebral inoculation of brain homogenate to tga20 mice overexpressing WT PrP, and from the latter to WT mice, but not to PrP-deficient mice. Upon successive transmissions, the incubation periods decreased and PrP became more protease-resistant, indicating the presence of a strain barrier that was gradually overcome by repeated passaging. This shows that expression of a subtly altered prion protein, with known 3D structure, efficiently generates a prion disease.

  • 125.
    Sigurdson, Christina J.
    et al.
    University of California San Diego.
    Nilsson, Peter
    University Hospital of Zurich.
    Hornemann, Simone
    University Hospital of Zurich.
    Manco, Guiseppe
    University Hospital of Zurich.
    Fernandez-Borges, Natalia
    University Hospital of Zurich.
    Schwarz, Petra
    University Hospital of Zurich.
    Castilla, Joaquin
    Basque Foundation for Science, Bizkaia, Spain.
    Wutrich, Kurt
    The Scripps Research Institute, La Jolla, California.
    Aguzzi, Adriano
    University Hospital of Zurich.
    A molecular switch controls interspeciesprion disease transmission in mice2010In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 120, p. 2590-2599Article in journal (Refereed)
    Abstract [en]

    Transmissible spongiform encephalopathies are lethal neurodegenerative disorders that present with aggregated forms of the cellular prion protein (PrPC), which are known as PrPSc. Prions from different species vary considerably in their transmissibility to xenogeneic hosts. The variable transmission barriers depend on sequence differences between incoming PrPSc and host PrPC and additionally, on strain-dependent conformational properties of PrPSc. The β22 loop region within PrPC varies substantially between species, with its structure being influenced by the residue types in the 2 amino acid sequence positions 170 (most commonly S or N) and 174 (N or T). In this study, we inoculated prions from 5 different species into transgenic mice expressing either disordered-loop or rigid-loop PrPC variants. Similar β22 loop structures correlated with efficient transmission, whereas dissimilar loops correlated with strong transmission barriers. We then classified literature data on cross-species transmission according to the 170S/N polymorphism. Transmission barriers were generally low between species with the same amino acid residue in position 170 and high between those with different residues. These findings point to a triggering role of the local β22 loop structure for prion transmissibility between different species.

  • 126. Sigurdson, C.J.
    et al.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Hornemann, S.
    Manco, G.
    Polymenidou, M.
    Schwarz, P.
    Leclerc, M.
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Wütrich, K.
    Aguzzi, A.
    Prion strain discrimination using luminescent conjugated polymers2007In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 4, no 12, p. 1023-1030Article in journal (Refereed)
    Abstract [en]

    The occurrence of multiple strains of prions may reflect conformational variability of PrPSc, a disease-associated, aggregated variant of the cellular prion protein, PrPC. Here we used luminescent conjugated polymers (LCPs), which emit conformation-dependent fluorescence spectra, for characterizing prion strains. LCP reactivity and emission spectra of brain sections discriminated among four immunohistochemically indistinguishable, serially mouse-passaged prion strains derived from sheep scrapie, chronic wasting disease (CWD), bovine spongiform encephalopathy (BSE), and mouse-adapted Rocky Mountain Laboratory scrapie prions. Furthermore, using LCPs we differentiated between field isolates of BSE and bovine amyloidotic spongiform encephalopathy, and identified noncongophilic deposits in prion-infected deer and sheep. We found that fibrils with distinct morphologies generated from chemically identical recombinant PrP yielded unique LCP spectra, suggesting that spectral characteristic differences resulted from distinct supramolecular PrP structures. LCPs may help to detect structural differences among discrete protein aggregates and to link protein conformational features with disease phenotypes.

  • 127.
    Simon, Rozalyn
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter R
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    pH-dependent optical transitions in anionic pentameric oligothiophenes2014Manuscript (preprint) (Other academic)
    Abstract [en]

    Understanding the photo-physical processes in fluorescent probes are essential as such dyes are widely utilized in molecular biology. Here we report the pH-dependent optical transitions of a library of anionic pentameric luminescent conjugated oligothiophenes (LCOs) that have been used for fluorescent identification of protein aggregates, the pathological hallmark of many devastating diseases. Absorption-, excitation- and emission spectra were recorded for all LCOs in different buffers with a pH range from 3.5 to 7. p-FTAA, a LCO having a central core consisting of a trimeric thiophene  building block with head-to-head acetic acid functionalization as well as terminal carboxyl groups extending the pentameric thiophene backbone, displayed pH/dependent optical characteristics correlating to a non-planar to planar transition of the conjugated backbone as well as aggregation between adjacent thiophene chain upon protonation of the  acetic acid side chains. In contrast, chemically related analogues to p-FTAA lacking the  terminal carboxyl groups extending the pentameric thiophene backbone or the conformational ability to undergo a non/planar to planar transition of the  conjugated backbone, displayed different optical characteristics compared to p-FTAA. Overall these studies highlighted that minor chemical alteration of LCOs can result in major difference in the optical characteristics obtained from the dyes and the results might aid in designing novel LCOs that have  superior optical performance as amyloid ligands.

  • 128.
    Simon, Rozalyn
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Optical reporting by conjugated polymers via conformational changes2010In: Advanced fluoroscence reporters in dhemistry and biology II / [ed] Demchenko, Alexander P., Springer Publishing Company, 2010, 1, p. 472-Chapter in book (Refereed)
    Abstract [en]

    This volume demonstrates the novel possibilities in sensing and imaging offered by the assembly of organic dyes into nanoparticles and nanocomposites and by the application of strongly fluorescent noble metal clusters and conjugated polymers. Its 14 chapters, written by top experts in this field, provide in-depth information on the coupling of organic dyes to different molecular and supramolecular structures, on their incorporation into polymeric nanoparticles and on the nanostructures that can be formed by some of the dyes. Bright and photostable several-atom clusters of gold and silver are examined. Finally, the revolutionary changes in sensing technologies attending the advent of conjugated polmyers and the advances in their application are discussed.

  • 129.
    Simon, Rozalyn
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Åslund, K. O. Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Haroutunian, Vahram
    Department of Psychiatry and Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York, USA.
    Gandy, Sam
    Department of Psychiatry and Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York, USA.
    Nilsson, Peter R
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Pentameric Thiophene-Based Ligands that Spectrally Discriminate Amyloid-b and Tau Aggregates Display Distinct Solvatochromism and Viscosity-Induced Spectral Shifts2014In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 39, p. 12537-12543Article in journal (Refereed)
    Abstract [en]

    A wide range of neurodegenerative diseases are characterized by the deposition of multiple protein aggregates. Ligands for molecular characterization and discrimination of these pathological hallmarks are thus important for understanding their potential role in pathogenesis as well as for clinical diagnosis of the disease. In this regard, luminescent conjugated oligothiophenes (LCOs) have proven useful for spectral discrimination of amyloid-beta (Aβ) and tau neurofibrillary tangles (NFTs), two of the pathological hallmarks associated with Alzheimer’s disease. Herein, the solvatochromism of a library of anionic pentameric thiophene-based ligands, as well as their ability to spectrally discriminate Aβ and tau aggregates, were investigated. Overall, the results from this study identified distinct solvatochromic and viscosity-dependent behavior of thiophene-based ligands that can be applied as indices to direct the chemical design of improved LCOs for spectral separation of Aβ and tau aggregates in brain tissue sections. The results also suggest that the observed spectral transitions of the ligands are due to their ability to conform by induced fit to specific microenvironments within the binding interface of each particular protein aggregate. We foresee that these findings might aid in the chemical design of thiophene-based ligands that are increasingly selective for distinct disease-associated protein aggregates.

  • 130.
    Sjölander, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Bijzet, Johan
    Department of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
    Hazenberg, Bouke P.
    Department of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Sensitive and rapid assessment of amyloid by oligothiophene fluorescence in subcutaneous fat tissue2015In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 22, no 1, p. 19-25Article in journal (Refereed)
    Abstract [en]

    Systemic amyloidosis (SA) is often diagnosed late. Combining clinical and biochemical biomarkers is necessary for raising suspicion of disease. Fine needle aspiration (FNA) of subcutaneous fat enables SA detection by Congo red staining. The luminescent conjugated probe heptameric formic thiophene acetic acid (h-FTAA) is a sensitive alternative to Congo red-staining of tissue samples. Our objective was to compare h-FTAA fluorescence with the Congo red stain for amyloid detection in FNA-obtained fat tissue. Herein, we studied samples from 57 patients with established SA (19 with AA, 20 with AL, and 18 with ATTR) and 17 age-matched controls (34–75 years). Positivity for h-FTAA was graded according to a Congo red-based grading scale ranging from 0 to 4+. Amyloid grading by both methods correlated strongly (r = 0.87). Here h-FTAA was positive in 53 of 54 Congo red-positive cases (sensitivity 98%) and h-FTAA was negative in 7 of 17 Congo red-negative controls (specificity 41%), but was also positive for 3 Congo red-negative SA cases. We conclude that h-FTAA fluorescence is more sensitive than Congo red staining in this small exploratory study of fat tissue samples, implicating potential sensitivity for prodromal amyloidosis, but is less specific for clinical amyloidosis defined by Congo red positivity. Given its simplicity h-FTAA staining may therefore be the most appropriate method for rapid screening of fat tissue samples but should presently treat grade 1+ as only suggestive, whereas 2+ or higher as positive for amyloidosis. Parallel assessment of h-FTAA and Congo red staining appears highly promising for clinical applications.

  • 131.
    Sjölander, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Mason, Jeffrey
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Westermark, G. T.
    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Westermark, P.
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Luminescent conjugated oligothiophenes: A novel dye for amyloid diagnostics2013In: XIIIth International Symposium on Amyloidosis: From Misfolded Proteins to Well-Designed Treatment: The Proceedings of the XIIIth International Symposium on Amyloidosis,May 6-10, 2012, Groningen, The Netherlands / [ed] Bouke P.C. Hazenberg and Johan Bijzet, GUARD (Groningen Unit for Amyloidosis Research & Development) , 2013, p. 179-182Conference paper (Refereed)
    Abstract [en]

    The alkaline Congo red staining method has, for almost half a century, been the gold standard of amyloid diagnosis. Unfortunately, the method is both laborious and requires great skill to achieve proper diagnosis. In this study we are presenting an alternative method that is compatible with immunofluorescence typing. We used a novel dye, h-FTAA, designed and synthesized by us. The dye belongs to the novel class of conformation sensitive dyes known as Luminescent conjugated oligothiophenes (LCOs). We examined 37 different cases of systemic amyloidoses from various tissues. It was found that h-FTAA binds to amyloid with higher sensitivity and greater selectivity than Congo red, as was determined by both fluorescence- and light polarization microscopy. Due to the methods ease of use and performance compared to Congo red, it is concluded that h-FTAA is a better first choice for screening of systemic amyloidoses.

  • 132.
    Sjölander, Daniel
    et al.
    Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Chemistry.
    Roecken, Christoph
    University of Kiel, Germany.
    Westermark, Per
    Uppsala University, Sweden.
    Westermark, Gunilla T.
    Uppsala University, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Establishing the fluorescent amyloid ligand h-FTAA for studying human tissues with systemic and localized amyloid2016In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 23, no 2, p. 98-108Article in journal (Refereed)
    Abstract [en]

    Rapid and accurate detection of amyloid deposits in routine surgical pathology settings are of great importance. The use of fluorescence microscopy in combination with appropriate amyloid specific dyes is very promising in this regard. Here we report that a luminescent conjugated oligothiophene, h-FTAA, rapidly and with high sensitivity and selectivity detects amyloid deposits in verified clinical samples from systemic amyloidosis patients with AA, AL and ATTR types; as well as in tissues laden with localized amyloidosis of AANF, AIAPP and ASem1 type. The probe h-FTAA emitted yellow red fluorescence on binding to amyloid deposits, whereas no apparent staining was observed in surrounding tissue. The only functional structure stained with h-FTAA showing the amyloidotypic fluorescence spectrum was Paneth cell granules in intestine. Screening of 114 amyloid containing tissues derived from 107 verified (Congo red birefringence and/or immunohistochemistry) amyloidosis patients revealed complete correlation between h-FTAA and Congo red fluorescence (107/107, 100% sensitivity). The majority of Congo red negative control cases (27 of 32, 85% specificity) were negative with h-FTAA. Small Congo red negative aggregates in kidney, liver, pancreas and duodenum were found by h-FTAA fluorescence in five control patients aged 72-83 years suffering from diverse diseases. The clinical significance of these false-positive lesions is currently not known. Because h-FTAA fluorescence is one magnitude brighter than Congo red and as the staining is performed four magnitudes lower than the concentration of dye, we believe that these inclusions are beyond detection by Congo red. We conclude that h-FTAA is a fluorescent hypersensitive, rapid and powerful tool for identifying amyloid deposits in tissue sections. Use of h-FTAA can be exploited as a rapid complementary technique for accurate detection of amyloid in routine surgical pathology settings. Our results also implicate the potential of the technique for detection of prodromal amyloidosis as well as for discovery of new amyloid-like protein aggregates in humans.

  • 133.
    Sjölander, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Röcken, Christoph
    Institute of Pathology, Christian-Albrechts-Univeristy, Kiel, Germany.
    Westermark, Per
    Department of Immunology, Uppsala University, Uppsala, Sweden.
    Westermark, Gunilla T.
    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Evaluation of the fluorescent amyloid ligand h-FTAA in human tissues with systemic and localized amyloid2014Manuscript (preprint) (Other academic)
    Abstract [en]

    Rapid and accurate detection of amyloid deposits in routine surgical pathology settings are of great importance. The use of fluorescence microscopy in combination with appropriate amyloid specific dyes is very promising in this regard. Most systemic amyloidosis are progressive and lethal. Disease specific therapy depends on the identification of the offending proteins. Here we report that a luminescent conjugated oligothiophene, h-FTAA, rapidly and with high sensitivity and selectivity detects amyloid deposits in verified clinical samples from systemic amyloidosis patients with AA, AL, and ATTR types; as well as in tissues laden with localized amyloidosis of AANF, AIAPP and ASem1 type. The probe h-FTAA emitted yellow red fluorescence on binding to amyloid deposits, whereas no apparent staining was observed in surrounding tissue. Screening of 114 amyloid containing tissues derived from §07 verified (Congo red birefringence and immunohistochemistry) amyloidosis patients revealed complete correlation between h-FTAA and Congo red fluorescence. We conclude that h-FTAA is a fluorescent hypersensitive, rapid and powerful tool for identifying amyloid deposits in tissue sections. H-FTAA staining can be utilized as a rapid complementary technique for accurate detection of amyloid in routine surgical pathology settings. It was also revealed that within 5 of 15 age matched Congo red negative control samples h-FTAA detects microdeposits of amyloid-like protein aggregates in liver and kidney. The results emphasize the potential of the dye for detection of prodromal amyloidosis as well as for discovery of novel amyloid-like protein aggregates in humans.

  • 134.
    Sjöqvist, Jonas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Computational Physics. Linköping University, The Institute of Technology.
    Maria, Jerôme
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Simon, Rozalyn
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Linares, Mathieu
    Linköping University, Department of Physics, Chemistry and Biology, Computational Physics. Linköping University, The Institute of Technology.
    Norman, Patrick
    Linköping University, Department of Physics, Chemistry and Biology, Computational Physics. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology. Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Toward a molecular understanding of the detection of amyloid proteins with flexible conjugated oligothiophenes2014In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 118, no 42, p. 9820-9827Article in journal (Refereed)
    Abstract [en]

    Molecular and electronic structures and optical absorption properties of oligothiophenes used for spectral assignment of amyloid deposits have been investigated for a family of probes known as luminescent conjugated oligothiophenes (LCOs). Theoretical absorption spectra have been determined using conformational averaging, combining classical molecular dynamics (MD) simulations with quantum mechanical/molecular mechanics (QM/MM) time-dependent density functional theory (TD-DFT) spectrum calculations. Theoretical absorption spectra are in excellent agreement with experiments, showing average errors below 5 nm for absorption maxima. To couple observed properties to molecular structures, a measure of planarity is defined, revealing a strong correlation between the transition wavelength of the first and dominating electronically excited state and dihedral rotations. It is shown that from this correlation, predictions can be made of the absorption properties of probes based only on information from MD trajectories. We show experimentally that red shifts observed in the excitation maxima of LCOs when bound to amyloid protein aggregates are also evident in absorption spectra. We predict that these red shifts are due to conformational restriction of the LCO in a protein binding pocket, causing a planarization of the conjugated backbone. On the basis of our studies of planarity, it is shown that such shifts are both possible and realistic.

  • 135.
    Snipstad, Sofie
    et al.
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Hak, Sjoerd
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
    Baghirov, Habib
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Sulheim, Einar
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway; SINTEF Materials and Chemistry, Trondheim, Norway.
    Mørch, Ýrr
    SINTEF Materials and Chemistry, Trondheim, Norway.
    Lélu, Sylvie
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    von Haartman, Eva
    Pharmaceutical Sciences Laboratory, Åbo Akademi University, Turku, Finland; Laboratory of Physical Chemistry, Åbo Akademi University, Turku, Finland.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, K. Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Klymchenko, Andrey S
    Laboratoire de Biophotonique et Pharmacologie, UMR CNRS 7213, Université de Strasbourg, Strasbourg, France.
    de Lange Davies, Catharina
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Åslund, Andreas K. O.
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Labeling nanoparticles: Dye leakage and altered cellular uptake2017In: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 91, no 8, p. 760-766Article in journal (Refereed)
    Abstract [en]

    In vitro and in vivo behavior of nanoparticles (NPs) is often studied by tracing the NPs with fluorescent dyes. This requires stable incorporation of dyes within the NPs, as dye leakage may give a wrong interpretation of NP biodistribution, cellular uptake, and intracellular distribution. Furthermore, NP labeling with trace amounts of dye should not alter NP properties such as interactions with cells or tissues. To allow for versatile NP studies with a variety of fluorescence-based assays, labeling of NPs with different dyes is desirable. Hence, when new dyes are introduced, simple and fast screening methods to assess labeling stability and NP-cell interactions are needed. For this purpose, we have used a previously described generic flow cytometry assay; incubation of cells with NPs at 4 and 37C. Cell-NP interaction is confirmed by cellular fluorescence after 37C incubation, and NP-dye retention is confirmed when no cellular fluorescence is detected at 4C. Three different NP-platforms labeled with six different dyes were screened, and a great variability in dye retention was observed. Surprisingly, incorporation of trace amounts of certain dyes was found to reduce or even inhibit NP uptake. This work highlights the importance of thoroughly evaluating every dye-NP combination before pursuing NP-based applications. © 2016 International Society for Advancement of Cytometry.

  • 136.
    Sole-Domenech, Santiago
    et al.
    Karolinska Institute, Sweden .
    Sjovall, Peter
    SP Technical Research Institute Sweden, Sweden .
    Vukojevic, Vladana
    Karolinska Institute, Sweden .
    Fernando, Ruani
    Hop St Eloi, France .
    Codita, Alina
    Karolinska Institute, Sweden .
    Salve, Sachin
    Karolinska Institute, Sweden .
    Bogdanovic, Nenad
    Karolinska Institute, Sweden .
    H Mohammed, Abdul
    Karolinska Institute, Sweden .
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    M LaFerla, Frank
    University of Calif Irvine, CA USA .
    Jacob, Stefan
    Karolinska Institute, Sweden .
    Berggren, Per-Olof
    Karolinska Institute, Sweden .
    Gimenez-Llort, Lydia
    University of Autonoma Barcelona, Spain .
    Schalling, Martin
    Karolinska Institute, Sweden .
    Terenius, Lars
    Karolinska Institute, Sweden .
    Johansson, Bjorn
    Karolinska Institute, Sweden .
    Localization of cholesterol, amyloid and glia in Alzheimers disease transgenic mouse brain tissue using time-of-flight secondary ion mass spectrometry (ToF-SIMS) and immunofluorescence imaging2013In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 125, no 1, p. 145-157Article in journal (Refereed)
    Abstract [en]

    The spatial distributions of lipids, amyloid-beta deposits, markers of neurons and glial cells were imaged, at submicrometer lateral resolution, in brain structures of a mouse model of Alzheimers disease using a new methodology that combines time-of-flight secondary ion mass spectrometry (ToF-SIMS) and confocal fluorescence microscopy. The technology, which enabled us to simultaneously image the lipid and glial cell distributions in Tg2576 mouse brain structures, revealed micrometer-sized cholesterol accumulations in hippocampal regions undergoing amyloid-beta deposition. Such cholesterol granules were either associated with individual amyloid deposits or spread over entire regions undergoing amyloidogenesis. Subsequent immunohistochemical analysis of the same brain regions showed increased microglial and astrocytic immunoreactivity associated with the amyloid deposits, as expected from previous studies, but did not reveal any particular astrocytic or microglial feature correlated with cholesterol granulation. However, dystrophic neurites as well as presynaptic vesicles presented a distribution similar to that of cholesterol granules in regions undergoing amyloid-beta accumulation, thus indicating that these neuronal endpoints may retain cholesterol in areas with lesions. In conclusion, the present study provides evidence for an altered cholesterol distribution near amyloid deposits that would have been missed by several other lipid analysis methods, and opens for the possibility to study in detail the putative liaison between lipid environment and protein structure and function in Alzheimers disease.

  • 137.
    Stavrinidou, Eleni
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Gabrielsson, Roger
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Nilsson, K. Peter R.
    Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Chemistry.
    Singh, Sandeep Kumar
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Franco- Gonzalez, Juan Felipe
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Volkov, Anton V.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Jonsson, Magnus P.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Grimoldi, Andrea
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Elgland, Mathias
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Zozoulenko, Igor V.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Simon, Daniel
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    In vivo polymerization and manufacturing of wires and supercapacitors in plants2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 11, p. 2807-2812Article in journal (Refereed)
    Abstract [en]

    Electronic plants, e-Plants, are an organic bioelectronic platform that allows electronic interfacing with plants. Recently we have demonstrated plants with augmented electronic functionality. Using the vascular system and organs of a plant, we manufactured organic electronic devices and circuits in vivo, leveraging the internal structure and physiology of the plant as the template, and an integral part of the devices. However, this electronic functionality was only achieved in localized regions, whereas new electronic materials that could be distributed to every part of the plant would provide versatility in device and circuit fabrication and create possibilities for new device concepts. Here we report the synthesis of such a conjugated oligomer that can be distributed and form longer oligomers and polymer in every part of the xylem vascular tissue of a Rosa floribunda cutting, forming long-range conducting wires. The plant’s structure acts as a physical template, whereas the plant’s biochemical response mechanism acts as the catalyst for polymerization. In addition, the oligomer can cross through the veins and enter the apoplastic space in the leaves. Finally, using the plant’s natural architecture we manufacture supercapacitors along the stem. Our results are preludes to autonomous energy systems integrated within plants and distribute interconnected sensor-actuator systems for plant control and optimization

  • 138.
    Storr, Tim
    et al.
    Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
    Dyrager, Christine
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
    Pinto Vieira, Rafael
    Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada(1);Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil(3);CAPES Foundation, Ministry of Education of Brazil, 70040-020 Brasília, DF, Brazil.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Synthesis and evaluation of benzothiazole-triazole and benzothiadiazole-triazole scaffolds as potential molecular probes for amyloid-β aggregation.2017In: New Journal of Chemistry, ISSN 1144-0546, E-ISSN 1369-9261, Vol. 41, no 4, p. 8p. 1566-1573Article in journal (Refereed)
    Abstract [en]

    Small-molecule ligands that bind to misfolded protein aggregates are essential tools for the study and detection of pathological hallmarks in neurodegenerative disorders, such as Alzheimer's disease (AD). In the present study, three compounds (one benzothiazole-triazole, L1, and two benzothiadiazole-triazoles, L2 and L3) were synthesized via a modular approach (azide–alkyne cycloaddition) and evaluated as potential ligands for amyloid-β (Aβ) aggregates. The binding to amyloid-like fibrils, generated from recombinant Aβ1–42, were studied and the binding specificity to amyloid deposits was evaluated in brain sections from transgenic mice with AD pathology. All three derivatives showed significant reduced emission in the presence of recombinant Aβ1–42 amyloid fibrils. In addition, the observed binding to Aβ deposits in tissue sections suggests that the benzothiazole-triazole and benzothiadiazole-triazole structures are promising molecular scaffolds that can be modified for binding to specific protein aggregates. [ABSTRACT FROM AUTHOR]

  • 139.
    Sörgjerd, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Wiseman, R. Luke
    Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, NY, USA.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Berg, Ina
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Budka, Herbert
    Institute of Neurology, Medical University of Vienna, Vienna, Austria.
    Nilsson, K. Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Ron, David
    Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, NY, USA.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    BiP can function as a molecular shepherd that alleviates oligomer toxicity and amass amyloidManuscript (Other academic)
    Abstract [en]

    A wide range of diseases are linked to protein misfolding and aggregation inside and outside the cell. It is of utmost interest to understand how the molecular chaperone machinery of the endoplasmic reticulum (ER) handles the expression of highly amyloidogenic proteins. We explored the hypothesis that the ER located Hsp70 molecular chaperone BiP plays a crucial role in amyloid diseases and influence the misfolding process and disease progression. We used the transthyretin mutant TTR D18G associated with an unusual central nervous system amyloid disease as the model substrate because it represents the most destabilized and degraded TTR variant known. Over-expression of TTR D18G in concert with BiP showed that BiP selectively recognize the amyloidogenic mutant protein as compared to wild type in human cells and collects the mutant in stable intermediate size oligomers within the ER. Furthermore, whereas TTR D18G was found to be highly cytotoxic to neuroblastoma cells, TTR D18G preincubated with BiP was non-toxic indicating that BiP protects the cell from cytotoxicity. BiP was also found present in cerebellar amyloid deposits and co-localized with TTR in a TTR D18G patient suggesting that the complex can be found in the extracellular space. We promote a fundamental role of BiP in misfolding diseases and describe a molecular shepharding function of BiP in sequestrating amyloidogenic protein molecules in benign oligomeric states.

  • 140.
    Ullsten, Sara
    et al.
    Uppsala University, Sweden.
    Bohman, Sara
    Uppsala University, Sweden.
    Oskarsson, Marie E.
    Uppsala University, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Westermark, Gunilla T.
    Uppsala University, Sweden.
    Carlsson, Per-Ola
    Uppsala University, Sweden.
    Islet amyloid deposits preferentially in the highly functional and most blood-perfused islets2017In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 6, no 7, p. 458-468Article in journal (Refereed)
    Abstract [en]

    Islet amyloid and beta cell death in type 2 diabetes are heterogeneous events, where some islets are affected early in the disease process, whereas others remain visibly unaffected. This study investigated the possibility that inter-islet functional and vascular differences may explain the propensity for amyloid accumulation in certain islets. Highly blood-perfused islets were identified by microspheres in human islet amyloid polypeptide expressing mice fed a high-fat diet for three or 10 months. These highly blood-perfused islets had better glucose-stimulated insulin secretion capacity than other islets and developed more amyloid deposits after 10 months of high-fat diet. Similarly, human islets with a superior release capacity formed more amyloid in high glucose culture than islets with a lower release capacity. The amyloid formation in mouse islets was associated with a higher amount of prohormone convertase 1/3 and with a decreased expression of its inhibitor proSAAS when compared to islets with less amyloid. In contrast, levels of prohormone convertase 2 and expression of its inhibitor neuroendocrine protein 7B2 were unaltered. A misbalance in prohormone convertase levels may interrupt the normal processing of islet amyloid polypeptide and induce amyloid formation. Preferential amyloid load in the most blood-perfused and functional islets may accelerate the progression of type 2 diabetes.

  • 141.
    Ulrich, Jason D.
    et al.
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    Ulland, Tyler K.
    Washington Univ, MO 63130 USA.
    Mahan, Thomas E.
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Song, Wilbur M.
    Washington Univ, MO 63130 USA.
    Zhou, Yingyue
    Washington Univ, MO 63130 USA.
    Reinartz, Mariska
    Washington Univ, MO 63110 USA; Radboud Univ Nijmegen, Netherlands.
    Choi, Seulah
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    Jiang, Hong
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    Stewart, Floy R.
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    Anderson, Elise
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    Wang, Yaming
    Washington Univ, MO 63130 USA; Eli Lilly and Co, IN 46285 USA.
    Colonna, Marco
    Washington Univ, MO 63130 USA.
    Holtzman, David M.
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    ApoE facilitates the microglial response to amyloid plaque pathology2018In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 215, no 4, p. 1047-1058Article in journal (Refereed)
    Abstract [en]

    One of the hallmarks of Alzheimers disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-beta (A beta) peptide. Apolipoprotein E (ApoE) influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric A beta in the brain. In addition to influencing A beta metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1 Delta E9 and APPPS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition, consistent with previous studies. However, fibrillar plaques in Apoe-deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct A beta morphotypes in Apoe-deficient mice. We also observed a significant reduction in fibrillar plaque-associated microgliosis and activated microglial gene expression in Apoe-deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology.

  • 142.
    Usmani, Shariq M.
    et al.
    Ulm University Medical Center, Germany .
    Zirafi, Onofrio
    Ulm University Medical Center, Germany .
    Mueller, Janis A.
    Ulm University Medical Center, Germany .
    Sandi-Monroy, Nathallie L.
    Ulm University Medical Center; Kinderwunsch-Zentrum Ulm, Germany.
    Yadav, Jay K.
    Ulm University, Germany.
    Meier, Christoph
    Ulm University, Germany .
    Weil, Tanja
    Ulm University, Germany.
    Roan, Nadia R.
    University of California at San Francisco, USA .
    Greene, Warner C.
    University of California at San Francisco, USA.
    Walther, Paul
    Ulm University, Germany.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Wetzel, Ronald
    University of Pittsburgh, PA, USA .
    Pilcher, Christopher D.
    University of California, San Francisco, USA .
    Gagsteiger, Friedrich
    Kinderwunsch-Zentrum Ulm, Germany.
    Fändrich, Marcus
    Ulm University, Germany.
    Kirchhoff, Frank
    Ulm University Medical Center, Germany.
    Münch, Jan
    Ulm University Medical Center, Germany.
    Direct visualization of HIV-enhancing endogenous amyloid fibrils in human semen2014In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, p. 3508-Article in journal (Refereed)
    Abstract [en]

    Naturally occurring fragments of the abundant semen proteins prostatic acid phosphatase ( PAP) and semenogelins form amyloid fibrils in vitro. These fibrils boost HIV infection and may play a key role in the spread of the AIDS pandemic. However, the presence of amyloid fibrils in semen remained to be demonstrated. Here, we use state of the art confocal and electron microscopy techniques for direct imaging of amyloid fibrils in human ejaculates. We detect amyloid aggregates in all semen samples and find that they partially consist of PAP fragments, interact with HIV particles and increase viral infectivity. Our results establish semen as a body fluid that naturally contains amyloid fibrils that are exploited by HIV to promote its sexual transmission.

  • 143.
    Wang, Bing
    et al.
    Univ Calif Santa Barbara, CA 93106 USA.
    Queenan, Bridget N.
    Univ Calif Santa Barbara, CA 93106 USA.
    Wang, Shu
    Chinese Acad Sci, Peoples R China.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Bazan, Guillermo C.
    Univ Calif Santa Barbara, CA 93106 USA.
    Precisely Defined Conjugated Oligoelectrolytes for Biosensing and Therapeutics2019In: Advanced Materials, ISSN 0935-9648, E-ISSN 1521-4095, Vol. 31, no 22, article id 1806701Article, review/survey (Refereed)
    Abstract [en]

    Conjugated oligoelectrolytes (COEs) are a relatively new class of synthetic organic molecules with, as of yet, untapped potential for use in organic optoelectronic devices and bioelectronic systems. COEs also offer a novel molecular approach to biosensing, bioimaging, and disease therapy. Substantial progress has been made in the past decade at the intersection of chemistry, materials science, and the biological sciences developing COEs and their polymer analogues, namely, conjugated polyelectrolytes (CPEs), into synthetic systems with biological and biomedical utility. CPEs have traditionally attracted more attention in arenas of sensing, imaging, and therapy. However, the precisely defined molecular structures and interactions of COEs offer potential key advantages over CPEs, including higher reliability and fluorescence quantum efficiency, larger diversity of subcellular targeting strategies, and improved selectivity to biomolecules. Here, the unique-and sometimes overlooked-properties of COEs are discussed and the noticeable progress in their use for biological sensing, imaging, and therapy is reviewed.

  • 144.
    Wegenast-Braun, Bettina M.
    et al.
    Hertie Institute Clin Brain Research, Germany German Centre Neurodegenerat Disease, Germany .
    Skodras, Angelos
    Hertie Institute Clin Brain Research, Germany German Centre Neurodegenerat Disease, Germany .
    Bayraktar, Gonca
    Hertie Institute Clin Brain Research, Germany University of Tubingen, Germany German Centre Neurodegenerat Disease, Germany .
    Mahler, Jasmin
    Hertie Institute Clin Brain Research, Germany University of Tubingen, Germany German Centre Neurodegenerat Disease, Germany .
    Fritschi, Sarah K.
    Hertie Institute Clin Brain Research, Germany University of Tubingen, Germany German Centre Neurodegenerat Disease, Germany .
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Mason, Jeffrey
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering.
    Liebig, Christian
    Hertie Institute Clin Brain Research, Germany German Centre Neurodegenerat Disease, Germany .
    Jucker, Mathias
    Hertie Institute Clin Brain Research, Germany German Centre Neurodegenerat Disease, Germany .
    Spectral Discrimination of Cerebral Amyloid Lesions after Peripheral Application of Luminescent Conjugated Oligothiophenes2012In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 181, no 6, p. 1953-1960Article in journal (Refereed)
    Abstract [en]

    In vivo imaging of pathological protein aggregates provides essential knowledge of the kinetics and implications of these lesions in the progression of proteopathies, such as Alzheimer disease. Luminescent conjugated oligothiophenes are amyloid-specific ligands that bind and spectrally distinguish different types of amyloid aggregates. Herein, we report that heptamer formyl thiophene acetic acid (hFTAA) passes the blood-brain barrier after systemic administration and specifically binds to extracellular beta-amyloid deposits in the brain parenchyma (A beta plaques) and in the vasculature (cerebral beta-amyloid angiopathy) of beta-amyloid precursor protein transgenic APP23 mice. Moreover, peripheral application of hFIAA also stained intracellular lesions of hyperphosphorylated Tau protein in P301S Tau transgenic mice. Spectral profiling of all three amyloid types was acquired ex vivo using two-photon excitation. hFTAA revealed a distinct shift in its emission spectra when bound to A beta plaques versus Tau lesions. Furthermore, a spectral shift was observed for A beta plaques versus cerebral beta-amyloid angiopathy, indicating that different amyloid types and structural variances of a specific amyloid type can be distinguished. In conclusion, by adding spectral signatures to amyloid lesions, our results pave the way for a new area of in vivo amyloid imaging, allowing in vivo differentiation of amyloid (sub)types and monitoring changes of their structure/composition over time. (Am J Pathol 2012, 181: 1953-1960 http://dx.doi.org/10.1016/j.ajpath.2012.08.031)

  • 145.
    Wickham, Abeni
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Sjölander, Daniel
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Bergström, Gunnar
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Wang, Ergang
    Chalmers, Sweden.
    Rajendran, Vijayalakshmi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hildesjö, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Skoglund, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Near-Infrared Emitting and Pro-Angiogenic Electrospun Conjugated Polymer Scaffold for Optical Biomaterial Tracking2015In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 25, no 27, p. 4274-4281Article in journal (Refereed)
    Abstract [en]

    Noninvasive tracking of biomaterials is vital for determining the fate and degradation of an implant in vivo, and to show its role in tissue regeneration. Current biomaterials have no inherent capacity to enable tracing but require labeling with, for example, fluorescent dyes, or nanoparticles. Here a novel biocompatible fully conjugated electrospun scaffold is described, based on a semiconducting luminescent polymer that can be visualized in situ after implantation using fluorescence imaging. The polymer, poly [2,3-bis-(3-octyloxyphenyl)quinoxaline-5,8-diyl-alt -thiophene-2,5-diyl] (TQ1), is electrospun to form a fibrous mat. The fibers display fluorescence emission in the near-infrared region with lifetimes in the sub-nanosecond range, optimal for in situ imaging. The material shows no cytotoxic behaviors for embryonic chicken cardiomyocytes and mouse myoblasts, and cells migrate onto the TQ1 fibers even in the presence of a collagen substrate. Subcutaneous implantations of the material in rats show incorporation of the TQ1 fibers within the tissue, with limited inflammation and a preponderance of small capillaries around the fibers. The fluorescent properties of the TQ1 fibers are fully retained for up to 90 d following implantation and they can be clearly visualized in tissue using fluorescence and lifetime imaging, thus making it both a pro-angiogenic and traceable biomaterial.

  • 146.
    Wigenius, Jens A.
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics . Linköping University, The Institute of Technology.
    Persson, Gustav
    Experimental Biomolecular Physics, Department of Applied Physics, Royal Institute of Technology, SE-106 91 Stockholm, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Widengren, Jerker
    Experimental Biomolecular Physics, Department of Applied Physics, Royal Institute of Technology, SE-106 91 Stockholm, Sweden.
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics . Linköping University, The Institute of Technology.
    Dark states in oligothiophenes: evidence from fluorescence correlation spectroscopy and dynamic light scatteringManuscript (preprint) (Other academic)
    Abstract [en]

    We report studies of the conjugated pentameric oligothiophene derivative p-FTAA, which changes optical properties in aqueous buffers of varying pH and concentration. Using dynamic light scattering, luminescence spectroscopy and fluorescence correlation spectroscopy, we find evidence for the formation of large clusters of p-FTAA in aqueous environment, formation of very large non-emissive clusters, and the presence of at least two dark transient states, one presumably being a triplet state. The clustering of p-FTAA is therefore an important mechanism. This work provides an interpretation of fluorescence spectra used for the detection of misfolding proteins through interaction with p-FTAA.

  • 147.
    Zako, T.
    et al.
    Bioengineering Laboratory, RIKEN Institute, Saitama, Japan.
    Kobayashi, T.
    Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
    Sakono, M.
    Bioengineering Laboratory, RIKEN Institute, Saitama, Japan.
    Lindgren, M.
    Department of Physics, The Norwegian University of Science and Technology, Trondheim, Norway.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Maeda, M.
    Bioengineering Laboratory, RIKEN Institute, Saitama, Japan.
    Structure and cytotoxicity of novel insulin noodle-like filamentous amyloids2009In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, no Suppl. s1, p. 173-173Article in journal (Other academic)
    Abstract [en]

    Insulin is a small peptide hormone that is known to form proteinassembly called amyloid fibrils under acidic conditions. We havepreviously shown that filamentous (‘noodle’-like) insulin amyloidwhich was morphologically different from fibrous (‘needle’-like)insulin amyloid was formed in the presence of a reducing agent,tris (2-carboxyethyl) phosphine hydrochloride (TCEP). The CDspectra showed that both of insulin fibrils and filaments containa beta-sheet structure. Nevertheless, Thioflavin T (ThT) bindingproperty was very different between them, suggesting a differencein inner structure. In this study, we examined their cell toxicitiesusing two different cell lines with MTT assay, and also examineddifference in their inner structures using novel luminescent conjugatedpolyelectrolyte probes (LCPs)1–4. The cytotoxicity of theinsulin filaments against rat PC12 and human HEK293 cell linewas also extremely low while the fibrils were toxic, suggestingthat the insulin filaments were generally nontoxic. This findingsupports the idea that cell toxicity of amyloids correlates withtheir morphology. The fluorescence measurement in the presenceof Polythiophene acetic acid (PTAA)1–4, one of the conformationsensitive LCPs, showed that PTAA weakly bound to the insulinfilaments and that the insulin fibrils’ spectrum revealed a spectral red shift in comparison to the PTAA-filaments interaction. Thissuggests that the insulin ‘noodle’-like filaments are formed byloose assembly of insulin molecules.

    References:

    1. Nilsson et al., Adv Mat 2008; 20: 2639.

    2. Chem Bio Chem 2006; 7:1096.

    3. ACS Chem Biol 2007; 4: 553.

    4. Sigurdson et al., Nature Methods 2007; 4: 1023.

  • 148.
    Zako, Tamotsu
    et al.
    Bioengineering Laboratory, RIKEN Institute, Wako, Saitama, Japan.
    Sakono, Masafumi
    Bioengineering Laboratory, RIKEN Institute, Wako, Saitama, Japan.
    Kobayashi, Takahiro
    Sörgjerd, Karin
    Bioengineering Laboratory, RIKEN Institute, Wako, Saitama, Japan.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, The Institute of Technology.
    Lindgren, Mikael
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Maeda, Mizuo
    Bioengineering Laboratory, RIKEN Institute, Wako, Saitama, Japan.
    Cell Interaction Study of Amyloid by Using Luminescent Conjugated Polythiophene: Implication that Amyloid Cytotoxicity Is Correlated withProlonged Cellular Binding2012In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 13, no 3, p. 358-363Article in journal (Refereed)
    Abstract [en]

    Needles and noodles: Studying amyloid toxicity is important for understanding protein misfolding diseases. Using a luminescent conjugated polythiophene, we found that cell binding of nontoxic filamentous amyloids of insulin and β2-microglobulin was less efficient than that of toxic fibrillar amyloids; this suggests a correlation between amyloid toxicity and cell binding.

  • 149.
    Zhang, Jun
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Sandberg, Alexander
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Konsmo, Audun
    Norwegian Univ Sci and Technol, Norway.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    LeVine, Harry III
    Univ Kentucky, KY 40536 USA.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Norwegian Univ Sci and Technol, Norway.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Detection and Imaging of A beta 1-42 and Tau Fibrils by Redesigned Fluorescent X-34 Analogues2018In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, no 28, p. 7210-7216Article in journal (Refereed)
    Abstract [en]

    We revisited the Congo red analogue 2,5-bis(4-hydroxy-3-carboxy-styryl)benzene (X-34) to develop this highly fluorescent amyloid dye for imaging Alzheimers disease (AD) pathology comprising A beta and Tau fibrils. A selection of ligands with distinct optical properties were synthesized by replacing the central benzene unit of X-34, with other heterocyclic moieties. Full photophysical characterization was performed, including recording absorbance and fluorescence spectra, Stokes shift, quantum yield and fluorescence lifetimes. All ligands displayed high affinity towards recombinant amyloid fibrils of A beta 1-42 (13-300nmK(d)) and Tau (16-200nmK(d)) as well as selectivity towards the corresponding disease-associated protein aggregates in AD tissue. We observed that these ligands efficiently displaced X-34, but not Pittsburgh compound B (PiB) from recombinant A beta 1-42 amyloid fibrils, arguing for retained targeting of the Congo red type binding site. We foresee that the X-34 scaffold offers the possibility to develop novel high-affinity ligands for A pathology found in human AD brain in a different mode compared with PiB, potentially recognizing different polymorphs of A fibrils.

  • 150.
    Åsberg, Peter
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Fluorescence quenching and excitation transfer between semiconducting and metallic organic layers2004In: Journal of Applied Physics, ISSN 0021-8979, E-ISSN 1089-7550, Vol. 96, no 6, p. 3140-3147Article in journal (Refereed)
    Abstract [en]

    Here we present a simple approach to study the interaction of singlet excitons with polarons in conjugated polymers in organic electronic devices. Interlayer quenching constants KIL of 1.5 M−1 between a fluorescent molecule and a doped polymer in a layered sample demonstrates the importance of understanding the quenching of excited states in polymeric devices. A combination of Förster resonance energy transfer and quenching of photoluminescence between a fluorescent molecule and a conjugated polymer in its semiconducting and metallic states were studied. The polymer is a chiral 3-substituted polythiophene (POWT) and the fluorescent molecule is fluorescein bound to dextran (D-FITC). Bilayer samples with fluorescein on top of the POWT were fabricated and studied with absorption spectroscopy, fluorescence microscopy, and electrochemical doping methods. When POWT is electrochemically dedoped it is possible to enhance the photoluminescence in the polymer layer by excitation transfer from the fluorescein layer. Our results demonstrate that PL from the polythiophene disappears rapidly as soon as the layer is doped. As the doping of polymer layer increases the fluorescence from the fluorescein on top of the polymer decreases, due to excitation quenching. Models for excitation transfer and excitation quenching in POWT/FITC bilayer devices have been developed. This model predicts a linear relationship between the PL from the two molecules, in agreement with our experimental findings. These results are relevant for the development of electroluminescent devices or solar cells based on conjugated polymers.

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