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  • 1.
    Aguilar-Calvo, Patricia
    et al.
    University of Calif San Diego, CA 92093 USA; University of Calif San Diego, CA 92093 USA.
    Xiao, Xiangzhu
    Case Western Reserve University, OH 44116 USA.
    Bett, Cyrus
    University of Calif San Diego, CA 92093 USA; University of Calif San Diego, CA 92093 USA; US FDA, MD USA.
    Erana, Hasier
    CIC bioGUNE, Spain.
    Soldau, Katrin
    University of Calif San Diego, CA 92093 USA.
    Castilla, Joaquin
    University of Calif San Diego, CA 92093 USA; CIC bioGUNE, Spain; Ikerbasque, Spain.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Surewicz, Witold K.
    Case Western Reserve University, OH 44116 USA.
    Sigurdson, Christina J.
    University of Calif San Diego, CA 92093 USA; University of Calif San Diego, CA 92093 USA; University of Calif Davis, CA 95616 USA.
    Post-translational modifications in PrP expand the conformational diversity of prions in vivo2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 43295Article in journal (Refereed)
    Abstract [en]

    Misfolded prion protein aggregates (PrPSc) show remarkable structural diversity and are associated with highly variable disease phenotypes. Similarly, other proteins, including amyloid-beta, tau, alpha-synuclein, and serum amyloid A, misfold into distinct conformers linked to different clinical diseases through poorly understood mechanisms. Here we use mice expressing glycophosphatidylinositol (GPI)anchorless prion protein, PrPC, together with hydrogen-deuterium exchange coupled with mass spectrometry (HXMS) and a battery of biochemical and biophysical tools to investigate how posttranslational modifications impact the aggregated prion protein properties and disease phenotype. Four GPI-anchorless prion strains caused a nearly identical clinical and pathological disease phenotype, yet maintained their structural diversity in the anchorless state. HXMS studies revealed that GPIanchorless PrPSc is characterized by substantially higher protection against hydrogen/deuterium exchange in the C-terminal region near the N-glycan sites, suggesting this region had become more ordered in the anchorless state. For one strain, passage of GPI-anchorless prions into wild type mice led to the emergence of a novel strain with a unique biochemical and phenotypic signature. For the new strain, histidine hydrogen-deuterium mass spectrometry revealed altered packing arrangements of beta-sheets that encompass residues 139 and 186 of PrPSc. These findings show how variation in posttranslational modifications may explain the emergence of new protein conformations in vivo and also provide a basis for understanding how the misfolded protein structure impacts the disease.

  • 2.
    Almstedt, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nyström, Sofie
    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.
    Amyloid fibrils of human prion protein are spun and woven from morphologically disordered aggregates2009In: Prion, ISSN 1933-6896, Vol. 3, no 4, p. 224-235Article in journal (Refereed)
    Abstract [en]

    Propagation and infectivity of prions in human prionopathies are likely associated with conversion of the mainly α-helical human prion protein, HuPrP, into an aggregated form with amyloid-like properties. Previous reports on efficient conversion of recombinant HuPrP have used mild to harsh denaturing conditions to generate amyloid fibrils in vitro. Herein we report on the in vitro conversion of four forms of truncated HuPrP (sequences 90-231 and 121-231 with and without an N-terminal hexa histidine tag) into amyloid-like fibrils within a few hours by using a protocol (phosphate buffered saline solutions at neutral pH with intense agitation) close to physiological conditions. The conversion process monitored by thioflavin T, ThT, revealed a three stage process with lag, growth and equilibrium phases. Seeding with preformed fibrils shortened the lag phase demonstrating the classic nucleated polymerization mechanism for the reaction. Interestingly, comparing thioflavin T kinetics with solubility and turbidity kinetics it was found that the protein initially formed non-thioflavionophilic, morphologically disordered aggregates that over time matured into amyloid fibrils. By transmission electron microscopy and by fluorescence microscopy of aggregates stained with luminescent conjugated polythiophenes (LCPs); we demonstrated that HuPrP undergoes a conformational conversion where spun and woven fibrils protruded from morphologically disordered aggregates. The initial aggregation functioned as a kinetic trap that decelerated nucleation into a fibrillation competent nucleus, but at the same time without aggregation there was no onset of amyloid fibril formation. The agitation, which was necessary for fibril formation to be induced, transiently exposes the protein to the air-water interface suggests a hitherto largely unexplored denaturing environment for prion conversion.

  • 3.
    Appelqvist, Hanna
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Stranius, Kati
    University of Gothenburg, Sweden.
    Börjesson, Karl
    University of Gothenburg, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Dyrager, Christine
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Specific Imaging of Intracellular Lipid Droplets Using a Benzothiadiazole Derivative with Solvatochromic Properties2017In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 28, no 5, p. 1363-1370Article in journal (Refereed)
    Abstract [en]

    Altered lipid metabolism and extensive lipid storage in cells have been associated with various medical disorders, including cancer. The development of fluorescent probes that specifically accumulate in lipid deposits is therefore of great interest in order to study pathological processes that are linked to dysregulated lipogenesis. In the present study, we present a small fluorescent benzothiadiazole dye that specifically stains lipid droplets in living and fixated cells. The photophysical characterization of the probe revealed strong solvatochromic behavior, large Stokes shifts, and high fluorescent quantum yields in hydrophobic solvents. In addition, the fluorophore exhibits a nontoxic profile and a high signal-to-noise ratio in cells (i.e., lipid droplets vs cytosol), which make it an excellent candidate for studying lipid biology using confocal fluorescent microscopy.

  • 4.
    Arja, Katriann
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology. Linköping, .
    Sjölander, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, Faculty of Science & Engineering. Linköping, .
    Åslund, Alma
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering. Linköping, .
    Prokop, Stefan
    Charite, Germany .
    Heppner, Frank L.
    Charite, Germany .
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering. Linköping, .
    Lindgren, Mikael
    Norwegian University of Science and Technology, Norway .
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, Faculty of Science & Engineering. Linköping, .
    Åslund, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering. Linköping, .
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering. Linköping, .
    Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand2013In: Macromolecular rapid communications, ISSN 1022-1336, E-ISSN 1521-3927, Vol. 34, no 9, p. 723-730Article in journal (Refereed)
    Abstract [en]

    Fluorescent probes identifying protein aggregates are of great interest, as deposition of aggregated proteins is associated with many devastating diseases. Here, we report that a fluorescent amyloid ligand composed of two distinct molecular moieties, an amyloidophilic pentameric oligothiophene and a porphyrin, can be utilized for spectral and lifetime imaging assessment of recombinant A 1-42 amyloid fibrils and A deposits in brain tissue sections from a transgenic mouse model with Alzheimers disease pathology. The enhanced spectral range and distinct lifetime diversity of this novel oligothiopheneporphyrin-based ligand allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye.

  • 5.
    Aslund, Andreas
    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.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Fluorescent oligo and poly-thiophenes and their utilization for recording biological events of diverse origin-when organic chemistry meets biology.2009In: Journal of chemical biology, ISSN 1864-6166, Vol. 2, no 4, p. 161-175Article in journal (Refereed)
    Abstract [en]

    The technique of using luminescent oligo-thiophenes and luminescent conjugated poly-thiophenes to monitor biological processes has gained increased interest from scientists within different research areas, ranging from organic chemistry and photo-physics to biology since its introduction. The technique is generally straightforward and requires only standard equipment, and the result is available within minutes from sample preparation. In this review, the syntheses of oligo and polythiophenes developed over the last decades are discussed. Furthermore, the utilization of these molecular agents for exploring biological events, e.g., DNA hybridization or protein misfolding events, are covered.

  • 6.
    Berg, Ina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    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.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Curcumin alleviates Aβ indcuced neurotoxicity and vice versa without removing amyloid deposits in transgenic DrosophilaManuscript (preprint) (Other academic)
    Abstract [en]

    Curcumin has been proposed to facilitate clearance of toxic amyloid formed by the Aβ peptide. To further address this notion, different concentrations of curcumin were tried for its effects in various Drosophila Alzheimer’s disease (AD) models. This study entailed five different Drosophila AD models (four Aβ expressing lines, and one tau expressing line), expressing the AD associated proteins using the Gal4/UAS system. These were assayed for several aspects of neurological impairment, including survival, climbing behavior, as well as locomotor activity. In addition, amyloid deposition was assessed by histological analysis. Curcumin treatment substantially prolonged the lifespan and improved climbing and locomotor activity for flies with severe disease geneotypes (Aβ1-42 E22G and double expressing Aβ1-42). In comparison, curcumin feeding of control flies resulted in a concentration-dependent shortened lifespan, whereas no such toxic side effects were found for AD genotypes with a mild phenotype (single expressors of Aβ1-40 and Aβ1-42). All flies expressing Aβ and tau displayed a higher total locomotor activity, and a continuation of the activity over a larger number of hours upon curcumin treatment. Unexpectedly, no change in tissue amyloid deposition upon curcumin treatment was observed. In vitro fibrillation of Aβ1-42, followed by Western blot and transmission electron microscopy in the presence and absence of curcumin, displayed enhanced fibrillation into large aggregates and decreased population of oligomers in curcumin samples. The decrease in oligomer formation by curcumin may explain why it increases the lifespan and activity without removing of the amyloid deposits seen in tissues. We also suggest that Aβ, at least in the context of Drosophila, functions as a chemical detoxifier sequestering curcumin and thereby mitigating its toxicity.

  • 7.
    Berg, Ina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, Faculty of Science & Engineering.
    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.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Efficient imaging of amyloid deposits in Drosophila models of human amyloidoses2010In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 5, no 5, p. 935-944Article in journal (Refereed)
    Abstract [en]

    Drosophila melanogaster is emerging as an important model system for neurodegenerative disease research. In this protocol, we describe an efficient method for imaging amyloid deposits in the Drosophila brain, by the use of a luminescent-conjugated oligothiophene (lco), p-Ftaa polymer probe. We also demonstrate the feasibility of co-staining with antibodies and compare the lco staining with standard amyloid-specific probes. the lco protocol enables high-resolution imaging of several different protein aggregates, such as aβ1-42, aβ1-42e22G, transthyretin V30M and human tau, in the Drosophila brain. aβ and tau aggregates could also be distinguished from each other because of distinct lco emission spectra. Furthermore, this protocol enables threedimensional brain mapping of amyloid distribution in whole-mount Drosophila brains. the use of p-Ftaa combined with other probes, antibodies and/or dyes will aid the rapid characterization of various amyloid deposits in the rapidly growing number of Drosophila models of neurodegenerative diseases.

  • 8.
    Bett, Cyrus
    et al.
    University of Calif San Diego, USA .
    Fernandez-Borges, Natalia
    Centre Cooperat Research Biosci CIC bioGUNE, Spain .
    Kurt, Timothy D.
    University of Calif San Diego, USA .
    Lucero, Melanie
    University of Calif San Diego, USA .
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Castilla, Joaquin
    Centre Cooperat Research Biosci CIC bioGUNE, Spain Basque Fdn Science IkerBasque, Spain .
    Sigurdson, Christina J.
    University of Calif San Diego, USA.
    Structure of the beta 2-alpha 2 loop and interspecies prion transmission2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 7, p. 2868-2876Article in journal (Refereed)
    Abstract [en]

    Prions are misfolded, aggregated conformers of the prion protein that can be transmitted between species. The precise determinants of interspecies transmission remain unclear, although structural similarity between the infectious prion and host prion protein is required for efficient conversion to the misfolded conformer. The beta 2-alpha 2 loop region of endogenous prion protein, PrPC, has been implicated in barriers to prion transmission. We recently discovered that conversion was efficient when incoming and host prion proteins had similar beta 2-alpha 2 loop structures; however, the roles of primary vs. secondary structural homology could not be distinguished. Here we uncouple the effect of primary and secondary structural homology of the beta 2-alpha 2 loop on prion conversion. We inoculated prions from animals having a disordered or an ordered beta 2-alpha 2 loop into mice having a disordered loop or an ordered loop due to a single residue substitution (D167S). We found that prion conversion was driven by a homologous primary structure and occurred independently of a homologous secondary structure. Similarly, cell-free conversion using PrPC from mice with disordered or ordered loops and prions from 5 species correlated with primary but not secondary structural homology of the loop. Thus, our findings support a model in which efficient interspecies prion conversion is determined by small stretches of the primary sequence rather than the secondary structure of PrP.

  • 9.
    Bett, Cyrus
    et al.
    Department of Pathology, University of California, San Diego, La Jolla, California, United States of America.
    Kurt, Tim D.
    Department of Pathology, University of California, San Diego, La Jolla, California, United States of America.
    Lucero, Melanie
    Department of Pathology, University of California, San Diego, La Jolla, California, United States of America.
    Trejo, Margarita
    Department of Neuroscience, University of California, San Diego, La Jolla, California, United States of America.
    Rozemuller, Annemieke J.
    Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands.
    Kong, Qingzhong
    Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Masliah, Eliezer
    Department of Neuroscience, University of California, San Diego, La Jolla, California, United States of America.
    Oldstone, Michael B.
    Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
    Sigurdson, Christina J.
    Department of Pathology, Immunology, and Microbiology, University of California, Davis, Davis, California, United States of America.
    Defining the Conformational Features of Anchorless, Poorly Neuroinvasive Prions2013In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 9, no 4Article in journal (Refereed)
    Abstract [en]

    Infectious prions cause diverse clinical signs and form an extraordinary range of structures, from amorphous aggregates to fibrils. How the conformation of a prion dictates the disease phenotype remains unclear. Mice expressing GPI-anchorless or GPI-anchored prion protein exposed to the same infectious prion develop fibrillar or nonfibrillar aggregates, respectively, and show a striking divergence in the disease pathogenesis. To better understand how a prion's physical properties govern the pathogenesis, infectious anchorless prions were passaged in mice expressing anchorless prion protein and the resulting prions were biochemically characterized. Serial passage of anchorless prions led to a significant decrease in the incubation period to terminal disease and altered the biochemical properties, consistent with a transmission barrier effect. After an intraperitoneal exposure, anchorless prions were only weakly neuroinvasive, as prion plaques rarely occurred in the brain yet were abundant in extracerebral sites such as heart and adipose tissue. Anchorless prions consistently showed very high stability in chaotropes or when heated in SDS, and were highly resistant to enzyme digestion. Consistent with the results in mice, anchorless prions from a human patient were also highly stable in chaotropes. These findings reveal that anchorless prions consist of fibrillar and highly stable conformers. The additional finding from our group and others that both anchorless and anchored prion fibrils are poorly neuroinvasive strengthens the hypothesis that a fibrillar prion structure impedes efficient CNS invasion.

  • 10.
    Björk, Per
    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, Organic Chemistry. Linköping University, The Institute of Technology.
    Lenner, Liselotte
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Kågedal, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Persson, Birgitta
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Conjugated polythiophene probes target lysosome-related acidic vacuoles in cultured primary cells2007In: Molecular and Cellular Probes, ISSN 0890-8508, Vol. 21, no 5-6, p. 329-337Article in journal (Refereed)
    Abstract [en]

    Conformation-sensitive optical probes for studying biological processes and structures are of great interest. The present work shows for the first time that conjugated polyelectrolyte (CPE) probes can be used for specific targeting of chromatin, nuclear and cytoplasmatic vesicles, and cytoskeletal components in a complex system of cultured cells. One of the probes could also be used for vital staining of live cells. When bound to different entities, the polythiophene derivative probes emitted light with different colors due to the unique spectral properties of these conformation sensitive probes. The physical pre-requisites for binding could also be exploited for characterization of the target. Unexpectedly, lysosome-related acidic vacuoles were targeted in cultured primary cells by both anionic, cationic, and zwitter-ionic polythiophene derivatives. Pre-treatment with Bafilomycin A1, a specific inhibitor of vacuolar-type H+-ATPase, caused redistribution of the staining. The targeting of lysosome-related acidic vesicles could not be demonstrated in transformed cells (melanoma, neuroblastoma, and prostate cancer cell lines), indicating a difference in the localization, structure, accessibility, or quantity of the target in cultured normal cells as compared with the malignant cell lines. The chemical nature of the conjugated polyelectrolyte complex in the cytoplasmatic vacuoles remains elusive.

  • 11.
    Björk, Per
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics . Linköping University, The Institute of Technology.
    Persson, Nils-Krister
    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.
    Åsberg, 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.
    Dynamics of complex formation between biological and luminescent conjugated polyelectrolytes - a surface plasmon resonance study2005In: Biosensors and Bioelectronics, ISSN 0956-5663, Vol. 20, no 9, p. 1764-1771Article in journal (Refereed)
    Abstract [en]

    A water-soluble polythiophene, POWT, with zwitterionic peptide like side chains possess good characteristics for biosensor applications. The zwitterionic side chains of the polymer can couple to biomolecules via electrostatic and hydrogen bonding. This creates possibilities to imprint biomolecules to spin-coated polymer films with maintained functionality, and use the resulting matrix as a biosensor. Polymer-biomolecular interaction studies done with surface plasmon resonance (SPR) reveal a well performing sensor matrix with high affinity for DNA hybridizations as well as for protein detection. The responses are distinct and very specific. A directional dependence of antibodies binding to POWT layer has also been observed. The polymer films have also been characterized by optical methods. Emission and absorption measurements in different buffer systems confirm that the polymer matrix can undergo structural and conformational changes on surfaces. The dielectric function in the interval 300–800 nm of POWT is reported, based on variable angle spectroscopic ellipsometry. This modeling reveals that a considerable amount of water is included in the material. The polymer layer possesses the characteristics needed for biochip applications and micro array techniques.

  • 12.
    Brelstaff, Jack
    et al.
    University of Cambridge, England.
    Ossola, Bernardino
    University of Cambridge, England.
    Neher, Jonas J.
    University of Tubingen, Germany.
    Klingstedt, Therese
    MRC, England.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Goedert, Michel
    MRC, England.
    Grazia Spillantini, Maria
    University of Cambridge, England.
    Tolkovsky, Aviva M.
    University of Cambridge, England.
    The fluorescent pentameric oligothiophene pFTAA identifies filamentous tau in live neurons cultured from adult P301S tau mice2015In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 9, no 184Article in journal (Refereed)
    Abstract [en]

    Identification of fluorescent dyes that label the filamentous protein aggregates characteristic of neurodegenerative disease, such as beta-amyloid and tau in Alzheimers disease, in a live cell culture system has previously been a major hurdle. Here we show that pentameric formyl thiophene acetic acid (pFTAA) fulfills this function in living neurons cultured from adult P301S tau transgenic mice. Injection of pFTAA into 5-month-old P301S tau mice detected cortical and DRG neurons immunoreactive for AT100, an antibody that identifies solely filamentous tau, or MC1, an antibody that identifies a conformational change in tau that is commensurate with neurofibrillary tangle formation in Alzheimers disease brains. In fixed cultures of dorsal root ganglion (DRG) neurons, pFTAA binding, which also identified AT100 or MC1+ve neurons, followed a single, saturable binding curve with a half saturation constant of 0.14 mu M, the first reported measurement of a binding affinity of a beta-sheet reactive dye to primary neurons harboring filamentous tau. Treatment with formic acid, which solubilizes filamentous tau, extracted pFTAA, and prevented the re-binding of pFTAA and MC1 without perturbing expression of soluble tau, detected using an anti-human tau (HT7) antibody. In live cultures, pFTAA only identified DRG neurons that, after fixation, were AT100/MC1+ve, confirming that these forms of tau pre-exist in live neurons. The utility of pFTAA to discriminate between living neurons containing filamentous tau from other neurons is demonstrated by showing that more pFTAA+ve neurons die than pFTAA-ve neurons over 25 days. Since pFTAA identifies fibrillar tau and other misfolded proteins in living neurons in culture and in animal models of several neurodegenerative diseases, as well as in human brains, it will have considerable application in sorting out disease mechanisms and in identifying diseasemodifying drugs that will ultimately help establish the mechanisms of neurodegeneration in human neurodegenerative diseases.

  • 13.
    Burns, R. E.
    et al.
    University of Calif San Diego, CA 92103 USA.
    Gaffney, P. M.
    University of Calif San Diego, CA 92103 USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Armien, A. G.
    University of Minnesota, MN 55108 USA.
    Pessier, A. P.
    University of Calif San Diego, CA 92103 USA.
    Systemic Amyloidosis in an African Tiger Snake (Telescopus semiannulatus)2017In: Journal of Comparative Pathology, ISSN 0021-9975, E-ISSN 1532-3129, Vol. 157, no 2-3, p. 136-140Article in journal (Refereed)
    Abstract [en]

    An adult male African tiger snake (Telescopts semiannulatus) was diagnosed with disseminated mycobacteriosis and a hepatic biliary cystadenocarcinoma. Histologically, the spleen was largely replaced by extracellular deposits of eosinophilic, fibrillar to hyaline material. Similar material was also present in the testicular interstitium and occasional blood vessel walls. This material was congophilic with strong green birefringence under polarized light and emitted fluorescence when bound to the luminescent-conjugated oligothiophene, h-FTAA, an amyloid binding probe. Ultrastructurally, deposits were composed of aggregates of haphazardly arranged, non-branching fibrils up to 8 nm in diameter and of indeterminate length. These findings all supported a diagnosis of amyloidosis, most likely amyloid A (AA) type based on concurrent inflammatory disease in this snake. However, immunohistochemistry for serum amyloid A was negative. There are only rare previous reports of amyloidosis in reptiles and many have been incompletely characterized. This case presents a thorough investigation into an occurrence of systemic amyloidosis in a snake, including a novel use of luminescent-conjugated oligothiophene binding in a reptile to confirm the diagnosis. (C) 2017 Elsevier Ltd. All rights reserved.

  • 14.
    Bäck, Marcus
    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.
    LeVine, Harry III
    University of Kentucky, KY 40536 USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Anionic Oligothiophenes Compete for Binding of X-34 but not PIB to Recombinant A beta Amyloid Fibrils and Alzheimers Disease Brain-Derived A beta2016In: CHEMISTRY-A EUROPEAN JOURNAL, ISSN 0947-6539, Vol. 22, no 51, p. 18335-18338Article in journal (Refereed)
    Abstract [en]

    Deposits comprised of amyloid- (A) are one of the pathological hallmarks of Alzheimers disease (AD) and small hydrophobic ligands targeting these aggregated species are used clinically for the diagnosis of AD. Herein, we observed that anionic oligothiophenes efficiently displaced X-34, a Congo Red analogue, but not Pittsburgh compoundB (PIB) from recombinant A amyloid fibrils and Alzheimers disease brain-derived A. Overall, we foresee that the oligothiophene scaffold offers the possibility to develop novel high-affinity ligands for A pathology only found in human AD brain, targeting a different site than PIB.

  • 15.
    Ceasar (Berg), Ina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, The Institute of Technology.
    Jonsson, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, The Institute of Technology.
    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.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, The Institute of Technology.
    Curcumin Promotes A-beta Fibrillation and Reduces Neurotoxicity in Transgenic Drosophila2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2Article in journal (Refereed)
    Abstract [en]

    The pathology of Alzheimers disease (AD) is characterized by the presence of extracellular deposits of misfolded and aggregated amyloid-beta (A beta) peptide and intraneuronal accumulation of tangles comprised of hyperphosphorylated Tau protein. For several years, the natural compound curcumin has been proposed to be a candidate for enhanced clearance of toxic A beta amyloid. In this study we have studied the potency of feeding curcumin as a drug candidate to alleviate A beta toxicity in transgenic Drosophila. The longevity as well as the locomotor activity of five different AD model genotypes, measured relative to a control line, showed up to 75% improved lifespan and activity for curcumin fed flies. In contrast to the majority of studies of curcumin effects on amyloid we did not observe any decrease in the amount of A beta deposition following curcumin treatment. Conformation-dependent spectra from p-FTAA, a luminescent conjugated oligothiophene bound to A beta deposits in different Drosophila genotypes over time, indicated accelerated pre-fibrillar to fibril conversion of A beta(1-42) in curcumin treated flies. This finding was supported by in vitro fibrillation assays of recombinant A beta(1-42). Our study shows that curcumin promotes amyloid fibril conversion by reducing the pre-fibrillar/oligomeric species of A beta, resulting in a reduced neurotoxicity in Drosophila.

  • 16.
    Choong, Ferdinand X.
    et al.
    Karolinska Inst, Sweden.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Schulz, Anette
    Karolinska Inst, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Edlund, Ulrica
    KTH Royal Inst Technol, Sweden.
    Richter-Dahlfors, Agneta
    Karolinska Inst, Sweden.
    Stereochemical identification of glucans by oligothiophenes enables cellulose anatomical mapping in plant tissues2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 3108Article in journal (Refereed)
    Abstract [en]

    Efficient use of plant-derived materials requires enabling technologies for non-disruptive composition analysis. The ability to identify and spatially locate polysaccharides in native plant tissues is difficult but essential. Here, we develop an optical method for cellulose identification using the structure-responsive, heptameric oligothiophene h-FTAA as molecular fluorophore. Spectrophotometric analysis of h-FTAA interacting with closely related glucans revealed an exceptional specificity for beta-linked glucans. This optical, non-disruptive method for stereochemical differentiation of glycosidic linkages was next used for in situ composition analysis in plants. Multi-laser/multi-detector analysis developed herein revealed spatial localization of cellulose and structural cell wall features such as plasmodesmata and perforated sieve plates of the phloem. Simultaneous imaging of intrinsically fluorescent components revealed the spatial relationship between cell walls and other organelles, such as chloroplasts and lignified annular thickenings of the trachea, with precision at the sub-cellular scale. Our non-destructive method for cellulose identification lays the foundation for the emergence of anatomical maps of the chemical constituents in plant tissues. This rapid and versatile method will likely benefit the plant science research fields and may serve the biorefinery industry as reporter for feedstock optimization as well as in-line monitoring of cellulose reactions during standard operations.

  • 17.
    Choong, Ferdinand X.
    et al.
    Karolinska Institute, Sweden.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Steiner, Svava E.
    Karolinska Institute, Sweden.
    Melican, Keira
    Karolinska Institute, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Edlund, Ulrica
    KTH Royal Institute Technology, Sweden.
    Richter-Dahlfors, Agneta
    Karolinska Institute, Sweden.
    Nondestructive, real-time determination and visualization of cellulose, hemicellulose and lignin by luminescent oligothiophenes2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 35578Article in journal (Refereed)
    Abstract [en]

    Enabling technologies for efficient use of the bio-based feedstock are crucial to the replacement of oil-based products. We investigated the feasibility of luminescent conjugated oligothiophenes (LCOs) for non-destructive, rapid detection and quality assessment of lignocellulosic components in complex biomass matrices. A cationic pentameric oligothiophene denoted p-HTEA (pentamer hydrogen thiophene ethyl amine) showed unique binding affinities to cellulose, lignin, hemicelluloses, and cellulose nanofibrils in crystal, liquid and paper form. We exploited this finding using spectrofluorometric methods and fluorescence confocal laser scanning microscopy, for sensitive, simultaneous determination of the structural and compositional complexities of native lignocellulosic biomass. With exceptional photostability, p-HTEA is also demonstrated as a dynamic sensor for real-time monitoring of enzymatic cellulose degradation in cellulolysis. These results demonstrate the use of p-HTEA as a non-destructive tool for the determination of cellulose, hemicellulose and lignin in complex biomass matrices, thereby aiding in the optimization of biomass-converting technologies.

  • 18.
    Chu, Tak-Ho
    et al.
    University of Calgary, Canada.
    Cummins, Karen
    University of Calgary, Canada.
    Sparling, Joseph S.
    University of Calgary, Canada.
    Tsutsui, Shigeki
    University of Calgary, Canada.
    Brideau, Craig
    University of Calgary, Canada.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Joseph, Jeffrey T.
    Alberta Health Serv, Canada.
    Stys, Peter K.
    University of Calgary, Canada.
    Axonal and myelinic pathology in 5xFAD Alzheimers mouse spinal cord2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, article id e0188218Article in journal (Refereed)
    Abstract [en]

    As an extension of the brain, the spinal cord has unique properties which could allow us to gain a better understanding of CNS pathology. The brain and cord share the same cellular components, yet the latter is simpler in cytoarchitecture and connectivity. In Alzheimers research, virtually all focus is on brain pathology, however it has been shown that transgenic Alzheimers mouse models accumulate beta amyloid plaques in spinal cord, suggesting that the cord possesses the same molecular machinery and conditions for plaque formation. Here we report a spatial-temporal map of plaque load in 5xFAD mouse spinal cord. We found that plaques started to appear at 11 weeks, then exhibited a time dependent increase and differential distribution along the cord. More plaques were found in cervical than other spinal levels at all time points examined. Despite heavy plaque load at 6 months, the number of cervical motor neurons in 5xFAD mice is comparable to wild type littermates. On detailed microscopic examination, fine beta amyloid-containing and beta sheet-rich thread-like structures were found in the peri-axonal space of many axons. Importantly, these novel structures appear before any plaque deposits are visible in young mice spinal cord and they co-localize with axonal swellings at later stages, suggesting that these thread-like structures might represent the initial stages of plaque formation, and could play a role in axonal damage. Additionally, we were able to demonstrate increasing myelinopathy in aged 5xFAD mouse spinal cord using the lipid probe Nile Red with high resolution. Collectively, we found significant amyloid pathology in grey and white matter of the 5xFAD mouse spinal cord which indicates that this structure maybe a useful platform to study mechanisms of Alzheimers pathology and disease progression.

  • 19.
    Cieslar-Pobuda, Artur
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Magnusson, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Vilas Jain, Mayur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Health Sciences.
    Ghavami, Saeid
    Manitoba Institute Child Heatlh, Canada; University of Manitoba, Canada .
    Nilsson, Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cell Type Related Differences in Staining with Pentameric Thiophene Derivatives2014In: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 85A, no 7, p. 628-635Article in journal (Refereed)
    Abstract [en]

    Fluorescent compounds capable of staining cells selectively without affecting their viability are gaining importance in biology and medicine. Recently, a new family of optical dyes, denoted luminescent conjugated oligothiophenes (LCOs), has emerged as an interesting class of highly emissive molecules for studying various biological phenomena. Properly functionalized LCOs have been utilized for selective identification of disease-associated protein aggregates and for selective detection of distinct cells. Herein, we present data on differential staining of various cell types, including cancer cells. The differential staining observed with newly developed pentameric LCOs is attributed to distinct side chain functionalities along the thiophene backbone. Employing flow cytometry and fluorescence microscopy we examined a library of LCOs for stainability of a variety of cell lines. Among tested dyes we found promising candidates that showed strong or moderate capability to stain cells to different extent, depending on target cells. Hence, LCOs with diverse imidazole motifs along the thiophene backbone were identified as an interesting class of agents for staining of cancer cells, whereas LCOs with other amino acid side chains along the backbone showed a complete lack of staining for the cells included in the study. Furthermore, for p-HTMI,a LCO functionalized with methylated imidazole moieties, the staining was dependent on the p53 status of the cells, indicating that the molecular target for the dye is a cellular component regulated by p53. We foresee that functionalized LCOs will serve as a new class of optical ligands for fluorescent classification of cells and expand the toolbox of reagents for fluorescent live imaging of different cells.

  • 20.
    Elgland, Mathias
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nordeman, P.
    Uppsala University, Sweden.
    Fyrner, Timmy
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Antoni, G.
    Uppsala University, Sweden.
    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.
    beta-Configured clickable [F-18] FDGs as novel F-18-fluoroglycosylation tools for PET2017In: New Journal of Chemistry, ISSN 1144-0546, E-ISSN 1369-9261, Vol. 41, no 18, p. 10231-10236Article in journal (Refereed)
    Abstract [en]

    In oncology and neurology the F-18-radiolabeled glucose analogue 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]FDG) is by far the most commonly employed metabolic imaging agent for positron emission tomography (PET). Herein, we report a novel synthetic route to beta-configured mannopyranoside precursors and a chemoselective F-18-fluoroglycosylation method that employ two b-configured [F-18]FDG derivatives equipped with either a terminal azide or alkyne aglycon respectively, for use as a CuAAC clickable tool set for PET. The b-configured precursors provided the corresponding [F-18]FDGs in a radiochemical yield of 77-88%. Further, the clickability of these [F-18]FDGs was investigated by click coupling to the suitably functionalized Fmoc-protected amino acids, Fmoc-N-(propargyl)-glycine and Fmoc-3-azido-L-alanine, which provided the F-18-fluoroglycosylated amino acid conjugates in radiochemical yields of 75-83%. The F-18-fluoroglycosylated amino acids presented herein constitute a new and interesting class of metabolic PET radiotracers.

  • 21.
    Falsig, Jeppe
    et al.
    Institute of Neuropathology, Zurich.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Knowles, Tuomas P J
    University of Cambridge.
    Aguzzi, Adriano
    Institute of Neuropathology, Zurich.
    Chemical and biophysical insights into the propagation of prion strains2008In: HFSP JOURNAL, ISSN 1955-2068, Vol. 2, no 6, p. 332-341Article in journal (Refereed)
    Abstract [en]

    Transmissible spongiform encephalopathies (TSEs) are lethal infectious neurodegenerative diseases. TSEs are caused by prions, infectious agents lacking informational nucleic acids, and possibly identical with higher-order aggregates of the cellular glycolipoprotein PrPC. Prion strains are derived from TSE isolates that, even after inoculation into genetically identical hosts, cause disease with distinct patterns of protein aggregate deposition, incubation times, morphology of the characteristic brain damage, and cellular tropism. Most of these traits are relatively stable across serial passages. Here we review current techniques for studying prion strain differences in vivo and in cells, and discuss the strain phenomena in the general context of the knowledge gained from modeling prion fibril growth in vitro and in simple organisms.

  • 22.
    Filippini, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, The Institute of Technology.
    Åsberg, Peter
    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.
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, The Institute of Technology.
    Computer screen photo-assisted spectral fingerprinting of luminescent polythiophene pH reporter2004In: IEEE Sensors. Proceedings, ISSN 1930-0395, E-ISSN 2168-9229, Vol. 3, p. 1377-1380Article in journal (Refereed)
    Abstract [en]

    The capability of the computer screen photo-assisted technique (CSPT)for the spectral fingerprinting of a photoactive polythiophene derivative (POWT) used as pH reporter is demonstrated. POWT is part of a family of industrial scalable materials, well established for organic electronics and biomedical applications, which is used here to demonstrate the capability of CSPT for tracing key spectral features. The ability of CSPTfor substance classification, corroborated by principal component analysis (PCA), successfully compares to standard spectroscopy, especially considering the involved equipments: CSPT is only a computer set and a web camera.

  • 23.
    Filippini, Daniel
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Applied Physics .
    Åsberg, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics .
    Nilsson, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics .
    Inganäs, Olle
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics .
    Lundström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Applied Physics .
    Computer screen photo-asssited detection of complementary DNA strands using a luminescent zwitterionic polythiophene derivative2006In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 1132006, p. 410-418Article in journal (Refereed)
  • 24. Frantz, S.E.A.
    et al.
    Mikael, L.A.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Inganäs, Olle
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics.
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Quantum efficiency and two-photon absorption cross-section of conjugated polyelectrolytes used for protein conformation measurements with applications on amyloid structures2007In: Chemical Physics, ISSN 0301-0104, E-ISSN 1873-4421, Vol. 336, no 2-3, p. 121-126Article in journal (Refereed)
    Abstract [en]

    Amyloid diseases such as Alzheimer's and spongiform encephalopathies evolve from aggregation of proteins due to misfolding of the protein structure. Early disease handling require sophisticated but yet simple techniques to follow the complex properties of the aggregation process. Conjugated polyelectrolytes (CPEs) have shown promising capabilities acting as optical biological sensors, since they can specifically bind to polypeptides both in solution and in solid phase. The structural changes in biomolecules can be monitored by changes of the optical spectra of the CPEs, both in absorption and emission modes. Notably, the studied CPEs possess multi-photon excitation capability, making them potential for in vivo imaging using laser scanning microscopy. Aggregation of proteins depends on concentration, temperature and pH. The optical effect on the molecular probe in various environments must also be investigated if applied in these environments. Here we present the results of quantum efficiency and two-photon absorption cross-section of three CPEs: POMT, POWT and PTAA in three different pH buffer systems. The extinction coefficient and quantum efficiency were measured. POMT was found to have the highest quantum efficiency being approximately 0.10 at pH 2.0. The two-photon absorption cross-section was measured for POMT and POWT and was found to be more than 18-25 times and 7-11 times that of Fluorescein, respectively. We also show how POMT fluorescence can be used to distinguish conformational differences between amyloid fibrils formed from reduced and non-reduced insulin in spectrally resolved images recorded with a laser scanning microscope using both one- and two-photon excitation. © 2007 Elsevier B.V. All rights reserved.

  • 25.
    Fritschi, Sarah K.
    et al.
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, Germany; University of Tubingen, Germany.
    Cintron, Amarallys
    Emory University, GA 30329 USA.
    Ye, Lan
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, Germany; University of Tubingen, Germany.
    Mahler, Jasmin
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, Germany; University of Tubingen, Germany.
    Buehler, Anika
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, Germany.
    Baumann, Frank
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, Germany.
    Neumann, Manuela
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, 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.
    Walker, Lary C.
    Emory University, GA 30329 USA; Emory University, GA 30322 USA.
    Jucker, Mathias
    German Centre Neurodegenerat Disease DZNE, Germany; University of Tubingen, Germany .
    A beta seeds resist inactivation by formaldehyde2014In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 128, no 4, p. 477-484Article in journal (Refereed)
    Abstract [en]

    Cerebral beta-amyloidosis can be exogenously induced by the intracerebral injection of brain extracts containing aggregated beta-amyloid (A beta) into young, pre-depositing A beta precursor protein- (APP) transgenic mice. Previous work has shown that the induction involves a prion-like seeding mechanism in which the seeding agent is aggregated A beta itself. Here we report that the beta-amyloid-inducing activity of Alzheimers disease (AD) brain tissue or aged APP-transgenic mouse brain tissue is preserved, albeit with reduced efficacy, after formaldehyde fixation. Moreover, spectral analysis with amyloid conformation-sensitive luminescent conjugated oligothiophene dyes reveals that the strain-like properties of aggregated A beta are maintained in fixed tissues. The resistance of A beta seeds to inactivation and structural modification by formaldehyde underscores their remarkable durability, which in turn may contribute to their persistence and spread within the body. The present findings can be exploited to establish the relationship between the molecular structure of A beta aggregates and the variable clinical features and disease progression of AD even in archived, formalin-fixed autopsy material.

  • 26.
    Fyrner, Timmy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering.
    Magnusson, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering.
    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.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Derivatization of a bioorthogonal protected trisaccharide linker: towards multimodal tools for chemical biology2012In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 23, no 6, p. 1333-1340Article in journal (Refereed)
    Abstract [en]

    When cross-linking biomolecules to surfaces or to other biomolecules, the use of appropriate spacer molecules is of great importance. Mimicking the naturally occurring spacer molecules will give further insight into their role and function, possibly unveil important issues regarding the importance of the specificity of carbohydrate-based anchor moieties, in e.g., glycoproteins and glycosylphosphatidylinositols. Herein, we present the synthesis of a lactoside-based trisaccharide, potentially suitable as a heterobifunctional bioorthogonal linker molecule whereon valuable chemical handles have been conjugated. An amino-derivative having thiol functionality shows promise as novel SPR-surfaces. Furthermore, the trisaccharide has been conjugated to a cholesterol moiety in combination with a fluorophore which successfully assemble on the cell surface in lipid microdomains, possibly lipid-rafts. Finally, a CuI-catalyzed azide-alkyne cycloaddition reaction (CuAAC) confirms the potential use of oligosaccharides as bioorthogonal linkers in chemical biology.

  • 27.
    Fändrich, M.
    et al.
    Ulm Univ, Germany.
    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.
    Bockmann, A.
    Univ Lyon, France.
    LeVine, H. III
    Univ Kentucky, KY 40536 USA; Univ Kentucky, KY USA.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Amyloid fibril polymorphism: a challenge for molecular imaging and therapy2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 3, p. 218-237Article in journal (Refereed)
    Abstract [en]

    The accumulation of misfolded proteins (MPs), both unique and common, for different diseases is central for many chronic degenerative diseases. In certain patients, MP accumulation is systemic (e.g. TTR amyloid), and in others, this is localized to a specific cell type (e.g. Alzheimers disease). In neurodegenerative diseases, NDs, it is noticeable that the accumulation of MP progressively spreads throughout the nervous system. Our main hypothesis of this article is that MPs are not only markers but also active carriers of pathogenicity. Here, we discuss studies from comprehensive molecular approaches aimed at understanding MP conformational variations (polymorphism) and their bearing on spreading of MPs, MP toxicity, as well as MP targeting in imaging and therapy. Neurodegenerative disease (ND) represents a major and growing societal challenge, with millions of people worldwide suffering from Alzheimers or Parkinsons diseases alone. For all NDs, current treatment is palliative without addressing the primary cause and is not curative. Over recent years, particularly the shape-shifting properties of misfolded proteins and their spreading pathways have been intensively researched. The difficulty in addressing ND has prompted most major pharma companies to severely downsize their nervous system disorder research. Increased academic research is pivotal for filling this void and to translate basic research into tools for medical professionals. Recent discoveries of targeting drug design against MPs and improved model systems to study structure, pathology spreading and toxicity strongly encourage future studies along these lines to provide an opportunity for selective imaging, prognostic diagnosis and therapy.

  • 28.
    Gabrielsson, Erik
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Armgarth, Astrid
    Linköping University, Department of Science and Technology, Physics and Electronics. 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.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Spatiotemporal Control of Amyloid-Like A Plaque Formation Using a Multichannel Organic Electronic Device2016In: Macromolecular materials and engineering (Print), ISSN 1438-7492, E-ISSN 1439-2054, Vol. 301, no 4, p. 359-363Article in journal (Refereed)
    Abstract [en]

    We herein report on an iontronic device to drive and control A1-40 and A1-42 fibril formation. This system allows kinetic control of A aggregation by regulation of H+ flows. The formed aggregates show both nanometer-sized fibril structure and microscopic growth, thus mimicking senile plaques, at the H+-outlet. Mechanistically we observed initial accumulation of A1-40 likely driven by electrophoretic migration which preceded nucleation of amyloid structures in the accumulated peptide cluster.

  • 29.
    Gabrielsson, Erik O.
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Armgarth, Astrid
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Nilsson, K. Peter N.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Controlled Microscopic Formation of Amyloid-Like Aβ Aggregates Using an Organic Electronic DeviceManuscript (preprint) (Other academic)
    Abstract [en]

    Alzheimer’s disease (AD), primarily associated with formation of fibrillar amyloid-beta peptide (Aβ) aggregates in the brain, is one of the most common old-age diseases. It is therefore crucial with an elevated scientific interest in Aβ, and its fundamental properties in a wide sense, to develop efficient methods for early detection and to combat AD. For the development of new techniques, both for AD detection and prevention, researchers are dependent on either tissue samples from deceased patients, animal models or in vitro systems. In vitro systems, such as producing protein aggregates of the Aβ-peptide in a test tube by incubation under denaturing conditions, offers us a simple but rather blunt tool for evaluating aggregation inhibition caused by compounds or to investigate new detection methods. We recently introduced the organic electronic ion pump (OEIP) as a method for creating amyloid-like aggregates at high spatiotemporal control as compared to the resulting aggregates manufactured using regular test tube-conditions. Combined with a fluorescent probe that is specific for the fibrillar aggregated form of misfolded peptides commonly seen in AD, this allowed us to control and to monitor the aggregation of a model peptide system in a highly confined space.

    To further elaborate the functionality of the OEIP together with amyloid-specific probes, we here present experiments demonstrating electronically controlled micron sized formation of Aβ-aggregates with morphologies ranging from fine fibers, to bundles of fibers, and thick mesh-like fiber structures. We foresee that the methodology can be implemented in multi array systems that can be utilized for studies of protein aggregation in confined spaces or together with cultured cells, as well as for the development of screening platforms for assessment of molecules influencing the Aβ-aggregation process.

  • 30.
    Gabrielsson, Erik O
    et al.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Tybrandt, Klas
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Berggren, Magnus
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Spatially Controlled Amyloid Reactions Using Organic Electronics2010In: SMALL, ISSN 1613-6810, Vol. 6, no 19, p. 2153-2161Article in journal (Refereed)
    Abstract [en]

    Abnormal protein aggregates, so called amyloid fibrils, are mainly known as pathological hallmarks of a wide range of diseases, but in addition these robust well-ordered self-assembled natural nanostructures can also be utilized for creating distinct nanomaterials for bioelectronic devices. However, current methods for producing amyloid fibrils in vitro offer no spatial control. Herein, we demonstrate a new way to produce and spatially control the assembly of amyloid-like structures using an organic electronic ion pump (OEIP) to pump distinct cations to a reservoir containing a negatively charged polypeptide. The morphology and kinetics of the created proteinaceous nanomaterials depends on the ion and current used, which we leveraged to create layers incorporating different conjugated thiophene derivatives, one fluorescent (p-FTAA) and one conducting (PEDOT-S). We anticipate that this new application for the OEIP will be useful for both biological studies of amyloid assembly and fibrillogenesis as well as for creating new bioelectronic nanomaterials and devices.

  • 31.
    Gallardo, Rodrigo
    et al.
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    Ramakers, Meine
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    De Smet, Frederik
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    Claes, Filip
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    Khodaparast, Ladan
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    Khodaparast, Laleh
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    Couceiro, Jose R.
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    Langenberg, Tobias
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    Siemons, Maxime
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Young, Laurence J.
    University of Cambridge, England; University of Leeds, England; University of Leeds, England.
    Laine, Romain F.
    University of Cambridge, England.
    Young, Lydia
    University of Cambridge, England; University of Leeds, England; University of Leeds, England.
    Radaelli, Enrico
    VIB Centre Biol Disease, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    Benilova, Iryna
    VIB Centre Biol Disease, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    Kumar, Manoj
    Katholieke University of Leuven, Belgium.
    Staes, An
    VIB, Belgium; University of Ghent, Belgium.
    Desager, Matyas
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    Beerens, Manu
    Katholieke University of Leuven, Belgium.
    Vandervoort, Petra
    Katholieke University of Leuven, Belgium.
    Luttun, Aernout
    Katholieke University of Leuven, Belgium.
    Gevaert, Kris
    VIB, Belgium; University of Ghent, Belgium.
    Bormans, Guy
    Katholieke University of Leuven, Belgium.
    Dewerchin, Mieke
    Katholieke University of Leuven, Belgium; VIB, Belgium.
    Van Eldere, Johan
    Katholieke University of Leuven, Belgium.
    Carmeliet, Peter
    Katholieke University of Leuven, Belgium; VIB, Belgium.
    Vande Velde, Greetje
    Katholieke University of Leuven, Belgium.
    Verfaillie, Catherine
    Katholieke University of Leuven, Belgium.
    Kaminski, Clemens F.
    University of Cambridge, England.
    De Strooper, Bart
    VIB Centre Biol Disease, Belgium; Katholieke University of Leuven, Belgium; Katholieke University of Leuven, Belgium.
    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.
    Serpell, Louise
    University of Sussex, England.
    Schymkowitz, Joost
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    Rousseau, Frederic
    VIB Switch Lab, Belgium; Katholieke University of Leuven, Belgium.
    De novo design of a biologically active amyloid2016In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 354, no 6313, p. 720-+Article in journal (Refereed)
    Abstract [en]

    Most human proteins possess amyloidogenic segments, but only about 30 are associated with amyloid-associated pathologies, and it remains unclear what determines amyloid toxicity. We designed vascin, a synthetic amyloid peptide, based on an amyloidogenic fragment of vascular endothelial growth factor receptor 2 (VEGFR2), a protein that is not associated to amyloidosis. Vascin recapitulates key biophysical and biochemical characteristics of natural amyloids, penetrates cells, and seeds the aggregation of VEGFR2 through direct interaction. We found that amyloid toxicity is observed only in cells that both express VEGFR2 and are dependent on VEGFR2 activity for survival. Thus, amyloid toxicity here appears to be both protein-specific and conditional-determined by VEGFR2 loss of function in a biological context in which target protein function is essential.

  • 32.
    Göransson, Anna-Lena
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Kanmert, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Nilsson, K. Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kågedal, Katarina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Identification of distinct physiochemical properties of the toxic prefibrillar species formed by Aβ peptide variants2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 420, no 4, p. 895-900Article in journal (Refereed)
    Abstract [en]

    The formation of amyloid-β peptide (Aβ) aggregates at an early stage during the self-assembly process is an important factor in the development of Alzheimer’s disease. The toxic effect is believed to be exerted by prefibrillar species of Aβ. It is therefore important to identify which prefibrillar species are toxic and characterize their distinct properties. In the present study, we investigated the in vitro aggregation behavior of Aβ-derived peptides possessing different levels of neurotoxic activity, using fluorescence spectroscopy in combination with transmission electron microscopy. The toxicity of various Aβ aggregates was assessed by using cultures of human neuroblastoma cells. Through combined use of the fluorescence probe 8-anilino-1-napthalenesulfonate (ANS) and the novel luminescent probe pentamer formyl thiophene acetic acid (p-FTAA), we were able to identify those Aβ peptide-derived prefibrillar species which exhibited cellular toxicity. In particular, species, which formed early during the aggregation process and showed strong p-FTAA and ANS fluorescence, were the species that possessed toxic activities. Moreover, by manipulating the aggregation conditions, it was possible to change the capacity of the Aβ peptide to form nontoxic versus toxic species.

  • 33.
    Göransson, Anna-Lena
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Otieno, Mildred
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Johansson, Leif B. G.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Nilsson, K. Peter R
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Dissecting the Aggregation Events of Alzheimer’s disease Associated Aβ peptide Variants by the Combined use of Different Fluorescent ProbesManuscript (preprint) (Other academic)
    Abstract [en]

    The formation of soluble prefibrillar oligomeric species of the amyloid β peptide (Aβ) has been implicated as a causative agent in the development of Alzheimer’s disease (AD). It is therefore important to characterize the properties of these aggregates, which precede the formation of amyloid fibrils. We studied the in vitro aggregation process of two Aβ40 peptide variants through the combined use of four different fluorescent probes and transmission electron microscopy. Previous studies have shown that these two studied Aβ40 variants exhibit different levels of neurodegeneration when expressed in the central nervous system of Drosophila melanogaster. In the present study, we demonstrate distinct differences in aggregate morphology and their binding properties to different fluorescent probes during in vitro fibrillation of these Aβ peptides. Our results indicate a potential link between the observed neurodegenerative properties and the biophysical properties of distinct aggregated Aβ species.

  • 34.
    Hahn, Katharina
    et al.
    Christian Albrechts University of Kiel, Germany.
    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.
    Urban, Peter
    Institute Pathol and Dermatopathol, Germany.
    Ruediger Meliss, Rolf
    Institute Dermatopathol, Germany.
    Behrens, Hans-Michael
    Christian Albrechts University of Kiel, Germany.
    Krueger, Sandra
    Christian Albrechts University of Kiel, Germany.
    Roecken, Christoph
    Christian Albrechts University of Kiel, Germany.
    Establishing and validating the fluorescent amyloid ligand h-FTAA (heptamer formyl thiophene acetic acid) to identify transthyretin amyloid deposits in carpal tunnel syndrome2017In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, no 2, p. 78-86Article in journal (Refereed)
    Abstract [en]

    Transthyretin-derived (ATTR) amyloidosis is a frequent finding in carpal tunnel syndrome. We tested the following hypotheses: the novel fluorescent amyloid ligand heptameric formic thiophene acetic acid (h-FTAA) has a superior sensitivity for the detection of amyloid compared with Congo red-staining; Amyloid load correlates with patient gender and/or patient age. We retrieved 208 resection specimens obtained from 184 patients with ATTR amyloid in the carpal tunnel. Serial sections were stained with Congo red, h-FTAA and an antibody directed against transthyretin (TTR). Stained sections were digitalized and forwarded to computational analyses. The amount of amyloid was correlated with patient demographics. Amyloid stained intensely with h-FTAA and an anti-TTR-antibody. Congo red-staining combined with fluorescence microscopy was significantly less sensitive than h-FTAA-fluorescence and TTR-immunostaining: the highest percentage area was found in TTR-immunostained sections, followed by h-FTAA and Congo red. The Pearson correlation coefficient was .8 (Congo red vs. h-FTAA) and .9 (TTR vs. h-FTAA). Amyloid load correlated with patient gender, anatomical site and patient age. h-FTAA is a highly sensitive method to detect even small amounts of ATTR amyloid in the carpal tunnel. The staining protocol is easy and h-FTAA may be a much more sensitive procedure to detect amyloid at an earlier stage.

  • 35.
    Hammarström, Per
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Simon, Rozalyn
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Åslund, Andreas
    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.
    A Fluorescent Pentameric Thiophene Derivative Detects in Vitro-Formed Prefibrillar Protein Aggregates2010In: BIOCHEMISTRY, ISSN 0006-2960, Vol. 49, no 32, p. 6838-6845Article in journal (Refereed)
    Abstract [en]

    Protein aggregation is associated with a wide range of diseases, and molecular probes that are able to detect a diversity of misfolded protein assemblies are of great importance. The identification of prefibrillar states preceding the formation of well-defined amyloid fibrils is of particular interest both because of their likely role in the mechanism of fibril formation and because of the growing awareness that these species are likely to play a critical role in the pathogenesis of protein deposition diseases. Herein, we explore the use of an anionic oligothiophene derivative, p-FTAA, for detection of prefibrillar protein aggregates during in vitro fibrillation of three different amyloidogenic proteins (insulin, lysozyme, and prion protein). p-FTAA generally detected prefibrillar protein aggregates that could not be detected by thioflavine T fluorescence and in addition showed high fluorescence when bound to mature fibrils. Second, the kinetics of protein aggregation or the formation of amyloid fibrils of insulin was not extensively influenced by the presence of various concentrations of p-FTAA. These results establish the use of p-FTAA as an additional tool for studying the process of protein aggregation.

  • 36.
    Heilbronner, Goetz
    et al.
    University of Tubingen, Germany .
    Eisele, Yvonne S.
    University of Tubingen, Germany .
    Langer, Franziska
    University of Tubingen, Germany .
    Kaeser, Stephan A.
    University of Tubingen, Germany .
    Novotny, Renata
    University of Tubingen, Germany .
    Nagarathinam, Amudha
    University of Tubingen, Germany .
    Åslund, Andreas
    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.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Jucker, Mathias
    University of Tubingen, Germany .
    Seeded strain-like transmission of beta-amyloid morphotypes in APP transgenic mice2013In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 14, no 11, p. 1017-1022Article in journal (Refereed)
    Abstract [en]

    The polymorphic beta-amyloid lesions present in individuals with Alzheimers disease are collectively known as cerebral beta-amyloidosis. Amyloid precursor protein (APP) transgenic mouse models similarly develop beta-amyloid depositions that differ in morphology, binding of amyloid conformation-sensitive dyes, and A beta 40/A beta 42 peptide ratio. To determine the nature of such beta-amyloid morphotypes, beta-amyloid-containing brain extracts from either aged APP23 brains or aged APPPS1 brains were intracerebrally injected into the hippocampus of young APP23 or APPPS1 transgenic mice. APPPS1 brain extract injected into young APP23 mice induced beta-amyloid deposition with the morphological, conformational, and A beta 40/A beta 42 ratio characteristics of beta-amyloid deposits in aged APPPS1 mice, whereas APP23 brain extract injected into young APP23 mice induced b-amyloid deposits with the characteristics of beta-amyloid deposits in aged APP23 mice. Injecting the two extracts into the APPPS1 host revealed a similar difference between the induced beta-amyloid deposits, although less prominent, and the induced deposits were similar to the beta-amyloid deposits found in aged APPPS1 hosts. These results indicate that the molecular composition and conformation of aggregated A beta in APP transgenic mice can be maintained by seeded conversion.

  • 37.
    Herland, Anna
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics . Linköping University, The Institute of Technology.
    Björk, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics . Linköping University, The Institute of Technology.
    Nilsson, K. Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics . Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. 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.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Electroactive luminescent self-assembled bio-organic nanowires: Integration of semiconducting oligoelectrolytes within amyloidogenic proteins2005In: Advanced Materials, ISSN 0935-9648, Vol. 17, no 12, p. 1466-1471Article in journal (Refereed)
  • 38.
    Herland, Anna
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics . Linköping University, The Institute of Technology.
    Nilsson, K. Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics . Linköping University, The Institute of Technology.
    Olsson, Johan D. M.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . 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.
    Synthesis of a regioregular zwitterionic conjugated oligoelectrolyte, usable as an optical probe for detection of amyloid fibril formation at acidic pH2005In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 127, no 7, p. 2317-2323Article in journal (Refereed)
    Abstract [en]

    Changes of the optical properties of conjugated polyelectrolytes have been utilized to monitor noncovalent interactions between biomolecules and the conjugated polyelectrolytes in sensor applications. A regioregular, zwitterionic conjugated oligoelectrolyte was synthesized in order to create a probe with a defined set of optical properties and hereby facilitate interpretation of biomolecule−oligoelectrolyte interactions. The synthesized oligoelectrolyte was used at acidic pH as a novel optical probe to detect amyloid fibril formation of bovine insulin and chicken lysozyme. Interaction of the probe with formed amyloid fibrils results in changes of the geometry and the electronic structure of the oligoelectrolyte chains, which were monitored with absorption and emission spectroscopy.

  • 39.
    Herrmann, Uli S.
    et al.
    University of Zurich Hospital, Switzerland.
    Schuetz, Anne K.
    ETH, Switzerland.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Huang, Danzhi
    University of Zurich, Switzerland.
    Saban, Dino
    University of Zurich Hospital, Switzerland.
    Nuvolone, Mario
    University of Zurich Hospital, Switzerland.
    Li, Bei
    University of Zurich Hospital, Switzerland.
    Ballmer, Boris
    University of Zurich Hospital, Switzerland.
    Åslund, Andreas
    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.
    Rushing, Elisabeth
    University of Zurich Hospital, Switzerland.
    Budka, Herbert
    University of Zurich Hospital, Switzerland.
    Nyström, Sofie
    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.
    Boeckmann, Anja
    University of Lyon 1, France.
    Caflisch, Amedeo
    University of Zurich, Switzerland.
    Meier, Beat H.
    ETH, Switzerland.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hornemann, Simone
    University of Zurich Hospital, Switzerland.
    Aguzzi, Adriano
    University of Zurich Hospital, Switzerland.
    Structure-based drug design identifies polythiophenes as antiprion compounds2015In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, no 299, p. 299ra123-Article in journal (Refereed)
    Abstract [en]

    Prions cause transmissible spongiform encephalopathies for which no treatment exists. Prions consist of PrPSc, a misfolded and aggregated form of the cellular prion protein (PrPC). We explore the antiprion properties of luminescent conjugated polythiophenes (LCPs) that bind and stabilize ordered protein aggregates. By administering a library of structurally diverse LCPs to the brains of prion-infected mice via osmotic minipumps, we found that antiprion activity required a minimum of five thiophene rings bearing regularly spaced carboxyl side groups. Solid-state nuclear magnetic resonance analyses and molecular dynamics simulations revealed that anionic side chains interacted with complementary, regularly spaced cationic amyloid residues of model prions. These findings allowed us to extract structural rules governing the interaction between LCPs and protein aggregates, which we then used to design a new set of LCPs with optimized binding. The new set of LCPs showed robust prophylactic and therapeutic potency in prion-infected mice, with the lead compound extending survival by greater than80% and showing activity against both mouse and hamster prions as well as efficacy upon intraperitoneal administration into mice. These results demonstrate the feasibility of targeted chemical design of compounds that may be useful for treating diseases of aberrant protein aggregation such as prion disease.

  • 40.
    Hornemann, S
    et al.
    Institute of Neuropathology, University Hospital Zurich, Zu¨ rich, Switzerland.
    Sponarova, J
    Institute of Neuropathology, University Hospital Zurich, Zu¨ rich, Switzerland.
    Zhu, C
    Institute of Neuropathology, University Hospital Zurich, Zu¨ rich, Switzerland.
    Finder, V
    Institute of Molecular Biology and Biophysics, Swiss Federal Institute of Technology, Zürich, Switzerland.
    Glockshuber, R
    Institute of Molecular Biology and Biophysics, Swiss Federal Institute of Technology, Zürich, Switzerland.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Aguzzi, A
    Institute of Neuropathology, University Hospital Zurich, Zürich, Switzerland.
    Mechanistic and structural aspects of the interaction of luminescent conjugated polymers with amyloid oligomers2010In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 17, no S1, p. 98-99Article in journal (Other academic)
    Abstract [en]

    Protein  misfolding  and aggregation  diseases, such as e.g. Alzheimer’s disease, are associated by the accumulation of a disease-related protein.  The pathogenic  mechanisms involved in these confor- mational diseases are only poorly understood. Luminescent-conjugated   polymers    (LCPs)     have been   shown   as  a  sensitive   tool   for  detection   of amyloid deposits. In contrast to commonly used amyloidotropic  dyes  such  as  thioflavins  or  Congo Red, LCPs are composed of flexible polythiophene chains which allow rotation  of the molecule.  Upon binding to amyloids, the LCPs alter their spectral properties  in a conformation dependent manner. However,  there  is still limited  information available on the binding  mechanism and binding  properties  of the LCPs  to amyloid fibrils and oligomers.

    We  have  produced  recombinant  human   Aβ1-42 (recAβ1-42) protein  in Escherichia coli and  purified it by conventional chromatographic techniques in large  quantities. The  recAβ-protein was  incubated in the presence  of SDS to induce formation  of homogenous, globular Aβ-oligomers  with a size of approximately   60  kDa,  known  as  Aβ-globulomers. We present  first biophysical  and  spectroscopic data used  to study  the  binding  and  structural properties of  the  complex   formed   by  the  globulomers   and LCPs  with various  charged  side chains.  These  data will  provide   a  more   detailed   knowledge   of  the binding    mode    of   amyloidogenic    probes    which is essential for understanding the structural char- acteristics    of   amyloid   fibrils   detected    by   thesemolecules.

  • 41.
    Johansson, Leif B. G.
    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.
    Lantz, Linda
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Eriksson, Mikaela
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nygren, Patrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    A variety of thiophene based ligands for detection of protein aggregates by surface plasmon resonanceManuscript (preprint) (Other academic)
    Abstract [en]

    By attaching an azide functional group via a tetraethylene glycol linker to the α-terminal position of a variety of oligothiophenes, thiophene-based ligands that can be utilized for detection of protein aggregates with surface plasmon resonance have been developed. All ligands displayed selectivity towards recombinant amyloid fibrils and the LCO/protein aggregate interaction could be detected by fluorescence as well as by surface plasmon resonance.

  • 42.
    Johansson, Leif B. G.
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Simon, Rozalyn
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Bergström, Gunnar
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Eriksson, Mikaela
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Prokop, Stefan
    Charite, Germany.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Heppner, Frank L.
    Charite, Germany.
    Åslund, Andreas
    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.
    An azide functionalized oligothiophene ligand - A versatile tool for multimodal detection of disease associated protein aggregates2015In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 63, p. 204-211Article in journal (Refereed)
    Abstract [en]

    Ligands for identifying protein aggregates are of great interest as such deposits are the pathological hallmark of a wide range of severe diseases including Alzheimers and Parkinsons disease. Here we report the synthesis of an azide functionalized fluorescent pentameric oligothiophene that can be utilized as a ligand for multimodal detection of disease-associated protein aggregates. The azide functionalization allows for attachment of the ligand to a surface by conventional click chemistry without disturbing selective interaction with protein aggregates and the oligothiophene-aggregate interaction can be detected by fluorescence or surface plasmon resonance. In addition, a methodology where the oligothiophene ligand is employed as a capturing molecule selective for aggregated proteins in combination with an antibody detecting a distinct peptide/protein is also presented. We foresee that this methodology will offer the possibility to create a variety of multiplex sensing systems for sensitive and selective detection of protein aggregates, the pathological hallmarks of several neurodegenerative diseases.

  • 43.
    Jonsson, Maria
    et al.
    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.
    Sandberg, Alexander
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Carlback, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Michno, Wojciech
    Univ Gothenburg, Sweden.
    Hanrieder, Jorg
    Univ Gothenburg, Sweden; UCL, England.
    Starkenberg, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. 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.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Aggregated A beta 1-42 Is Selectively Toxic for Neurons, Whereas Glial Cells Produce Mature Fibrils with Low Toxicity in Drosophila2018In: Cell Chemical Biology, ISSN 2451-9456, E-ISSN 2451-9448, Vol. 25, no 5, p. 595-610Article in journal (Refereed)
    Abstract [en]

    The basis for selective vulnerability of certain cell types for misfolded proteins (MPs) in neurodegenerative diseases is largely unknown. This knowledge is crucial for understanding disease progression in relation to MPs spreading in the CNS. We assessed this issue in Drosophila by cell-specific expression of human A beta 1-42 associated with Alzheimers disease. Expression of A beta 1-42 in various neurons resulted in concentration-dependent severe neurodegenerative phenotypes, and intraneuronal ringtangle-like aggregates with immature fibril properties when analyzed by aggregate-specific ligands. Unexpectedly, expression of A beta 1-42 from a pan-glial driver produced a mild phenotype despite massive brain load of A beta 1-42 aggregates, even higher than in the strongest neuronal driver. Glial cells formed more mature fibrous aggregates, morphologically distinct from aggregates found in neurons, and was mainly extracellular. Our findings implicate that A beta 1-42 cytotoxicity is both cell and aggregate morphotype dependent.

  • 44.
    Karlsson, Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Åsberg, Peter
    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.
    Interactions between a zwitterionic polythiophene derivative and oligonucleotides as resolved by fluorescence resonance energy transfer2005In: Chemistry of Materials, ISSN 0897-4756, E-ISSN 1520-5002, Vol. 17, no 16, p. 4204-4211Article in journal (Refereed)
    Abstract [en]

    The interactions between a zwitterionic polythiophene derivative, POWT, and DNA oligonucleotides in solution have been studied by FRET (fluorescence resonance energy transfer). When POWT and ssDNA are bound alone in a complex, the distance between them is at its smallest. The distance increases when adding complementary DNA, but POWT is still mainly bound to the first DNA strand. We find that two POWT chains bind to one DNA strand, and the two POWT chains seem held together in pairs, unable to separate, as they can only bind to and quench half their own amount of labeled DNA. This POWT−POWT complex appears to dissociate at lower concentrations. ssDNA attached to POWT in a complex can also be substituted by other ssDNA in solution; this occurs to 50% when the free DNA is present in 10-fold concentration compared to the ssDNA bound to POWT. Titration studies at different concentrations show positive cooperativity in the binding of POWT and ssDNA into a complex. The hybridization of complementary DNA to the same complex involves no cooperativity. These observations indicate interesting possibilities for the use of POWT as a DNA sensor.

  • 45.
    Khodaparast, Ladan
    et al.
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Khodaparast, Laleh
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Gallardo, Rodrigo
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Louros, Nikolaos N.
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Michiels, Emiel
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Ramakrishnan, Reshmi
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Ramakers, Meine
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Claes, Filip
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Young, Lydia
    Univ Leeds, England; Univ Leeds, England.
    Shahrooei, Mohammad
    KULeuven, Belgium.
    Wilkinson, Hannah
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Desager, Matyas
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Tadesse, Wubishet Mengistu
    KULeuven, Belgium.
    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.
    Aertsen, Abram
    KULeuven, Belgium.
    Carpentier, Sebastien
    KULeuven, Belgium.
    Van Eldere, Johan
    KULeuven, Belgium.
    Rousseau, Frederic
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Schymkowitz, Joost
    SWITCH Lab, Belgium; KULeuven, Belgium.
    Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 866Article in journal (Refereed)
    Abstract [en]

    Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow. In addition, the approach is effective against drug-resistant clinical isolates of Escherichia coli and Acinetobacter baumannii, reducing bacterial load in a murine bladder infection model. Our results indicate that redundant APRs are weak points of bacterial protein homeostasis and that targeting these may be an attractive antibacterial strategy.

  • 46.
    Klingstedt, Therése
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Blechschmidt, Cristiane
    Charite, Germany .
    Nogalska, Anna
    University of So Calif, CA USA .
    Prokop, Stefan
    Charite, Germany .
    Häggqvist, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Danielsson, Olof
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    King Engel, W
    University of So Calif, CA USA .
    Askanas, Valerie
    University of So Calif, CA USA .
    Heppner, Frank L.
    Charite, Germany .
    Nilsson, K Peter R
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Luminescent Conjugated Oligothiophenes for Sensitive Fluorescent Assignment of Protein Inclusion Bodies2013In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 14, no 5, p. 607-616Article in journal (Refereed)
    Abstract [en]

    Small hydrophobic ligands identifying intracellular protein deposits are of great interest, as protein inclusion bodies are the pathological hallmark of several degenerative diseases. Here we report that fluorescent amyloid ligands, termed luminescent conjugated oligothiophenes (LCOs), rapidly and with high sensitivity detect protein inclusion bodies in skeletal muscle tissue from patients with sporadic inclusion body myositis (s-IBM). LCOs having a conjugated backbone of at least five thiophene units emitted strong fluorescence upon binding, and showed co-localization with proteins reported to accumulate in s-IBM protein inclusion bodies. Compared with conventional amyloid ligands, LCOs identified a larger fraction of immunopositive inclusion bodies. When the conjugated thiophene backbone was extended with terminal carboxyl groups, the LCO revealed striking spectral differences between distinct protein inclusion bodies. We conclude that 1) LCOs are sensitive, rapid and powerful tools for identifying protein inclusion bodies and 2) LCOs identify a wider range of protein inclusion bodies than conventional amyloid ligands.

  • 47.
    Klingstedt, Therése
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Kostareva, A
    Almazov Federal Centre of Heart, Blood and Endocrinology, St. Petersburg, Russian Federation.
    Sjöberg, G.
    Karolinska Institute, Stockholm, Sweden.
    Gudkova, A
    Almazov Federal Centre of Heart, Blood and Endocrinology, St. Petersburg, Russian Federation.
    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.
    Sejersen, T
    Karolinska Institute, Stockholm, Sweden.
    Desmin L345P transgenic mice exhibit morphological and biochemical features of amyloidosis of two distinct types2010In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 31, no Suppl. 1, p. 924-925Article in journal (Other academic)
    Abstract [en]

    Background: Being a chief intermediate filament of the muscle tissue, desmin isimplicated in the sarcomeric organization, organelle positioning and mitochondrialfunction. Various desmin mutations have been reported as a possible cause forcardiomyopathies. Several reports on transgenic mice expressing mutant desminshowed deleterious effects of mutant desmin incorporated into filaments on cardiomyocyte function, but most importantly that accumulation of unfolded proteinaggregates plays an important pathogenic role in development of desminassociatedcardiomyopathies. Thus, in desmin transgenic mice with the L345Pmutation, which interferes in a dominant-negative manner with desmin polymerization,the accumulation of intracellular and extracellular amyloidogenic proteinaggregates was shown to be the key feature along with alteration of mitochondrialstructure and function. Therefore, the aim of this study was to characterizethe nature of amyloidogenic protein aggregates in L345P desmin transgenic miceon molecular and protein level.

    Material and methods: L345P desmin transgenic mice (DM) and WT mice 40weeks old were analyzed. Myocardial cryostat 10 micron sections were stainedwith conventional techniques (hematoxilin-eosin, Congo Red). A detailed amyloidcharacterization was carried out using novel optical probes called luminescentconjugated oligothiophenes and polythiophenes (LCOs and LCPs) that specificallystain various protein aggregates and give rise to conformation dependentemission spectra.

    Results: The most prominent feature of DM mice myocardium was misfoldedprotein depositions in perivascular space and between muscle fibers. Analysisof samples from DM mouse stained with LCO or LCP revealed the presence ofaggregates emitting light with two different emission spectra. Since the spectralproperties of the LCOs or LCPs are dependent on their conformation, the appearanceof two dissimilar emission spectra indicates that the probes might bindto two different types of amyloid aggregates within the tissue. Interestingly, aggregateswith emission spectra similar to one of the two types found in the DMmouse could also be found in WT mice, but in a much lower extent, suggesting asporadic cardiac amyloid pathology in C57 Bl/6 mice at 40 weeks, probably, as anative aging attribute.

    Conclusions: The L345P desmin mutation causes focal amyloid protein depositionin heart muscle of two distinct types. White first one can be a natural attributeof C57 Bl/6 mice detected with age, another one can be specifically responsiblefor the development of desmin-related cardiomyopathy.

  • 48.
    Klingstedt, Therése
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Conjugated polymers for enhanced bioimaging2011In: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, ISSN 0304-4165, Vol. 1810, no 3, p. 286-296Article, review/survey (Refereed)
    Abstract [en]

    Background: Conjugated polymers (CPs) have been used for creating bioimaging tools or biosensors that provide a direct link between spectral signal and different biological processes. The detection schemes of these sensors are mainly employing the efficient light harvesting properties or the conformation sensitive optical properties of the CPs. Hence, the presence of biomolecules or biological events can be detected through fluorescence resonance energy transfer (FRET) between the CP and an acceptor molecule, or through their impact on the conformation of the conjugated backbone, which is seen as an alteration of the optical properties of the CP. Scope of the review: In this review, the utilization of CPs for sensitive detection of DNA and protein conformational changes will be presented. The main part will be focused on the specific binding of CPs to protein deposits associated with protein misfolding diseases, such as Alzheimers disease (AD), and the discovery that tailor-made CPs can be used for in vivo optical imaging of protein aggregates will be discussed. Major conclusions: The unique optical properties of CPs can be used as molecular tools for sensitive detection of genetic material and for characterization of the pathological hallmarks associated with protein misfolding disorders, such as AD. General significance: CPs are novel molecular tools that can be used for sensitive bioimaging of biological processes and these tools offer the possibility to study biological events in a complementary fashion to conventional techniques. This article is part of a Special Issue entitled Nanotechnologies - Emerging Applications in Biomedicine.

  • 49.
    Klingstedt, Therése
    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.
    Luminescent conjugated poly- and oligo-thiophenes: optical ligands for spectral assignment of a plethora of protein aggregates2012In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 40, p. 704-710Article in journal (Refereed)
    Abstract [en]

    The deposition of protein aggregates in various parts of our body gives rise to several devastating diseases, and the development of probes for the selective detection of aggregated proteins is crucial to advance our understanding of the pathogenesis underlying these diseases. LCPs (luminescent conjugated polythiophenes) are fluorescent probes that bind selectively to protein aggregates. The conjugated thiophene backbone is flexible and offers a connection between the conformation and the emission properties, hence binding of LCPs gives the molecule a spectral fingerprint. The present review covers the utilization of LCPs to study the heterogeneity of protein aggregates. It emphasizes specifically the introduction of well-defined probes called LCOs (luminescent conjugated oligothiophenes) and reports how these molecules can be used for real-time in vivo imaging of cerebral plaques as well as for spectral discrimination of protein aggregates and detection of early species in the fibrillation pathway of amyloid beta-peptide.

  • 50.
    Klingstedt, Therése
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Mahler, Jasmin
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Wegenast-Braun, Bettina M.
    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.
    Goedert, Michel
    MRC, England.
    Jucker, Mathias
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Distinct Spacing Between Anionic Groups: An Essential Chemical Determinant for Achieving Thiophene-Based Ligands to Distinguish Beta-Amyloid or Tau Polymorphic Aggregates2015In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 25, p. 9072-9082Article in journal (Refereed)
    Abstract [en]

    The accumulation of protein aggregates is associated with many devastating neurodegenerative diseases and the existence of distinct aggregated morphotypes has been suggested to explain the heterogeneous phenotype reported for these diseases. Thus, the development of molecular probes able to distinguish such morphotypes is essential. We report an anionic tetrameric oligothiophene compound that can be utilized for spectral assignment of different morphotypes of -amyloid or tau aggregates present in transgenic mice at distinct ages. The ability of the ligand to spectrally distinguish between the aggregated morphotypes was reduced when the spacing between the anionic substituents along the conjugated thiophene backbone was altered, which verified that specific molecular interactions between the ligand and the protein aggregate are necessary to detect aggregate polymorphism. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between different morphotypes of protein aggregates.

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