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  • 1.
    Aguilar-Calvo, Patricia
    et al.
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Bett, Cyrus
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Sevillano, Alejandro M.
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Kurt, Timothy D.
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Lawrence, Jessica
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Soldau, Katrin
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    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.
    Sigurdson, Christina J.
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA; Univ Calif Davis, CA USA.
    Generation of novel neuroinvasive prions following intravenous challenge2018In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, no 6, p. 999-1011Article in journal (Refereed)
    Abstract [en]

    Prions typically spread into the central nervous system (CNS), likely via peripheral nerves. Yet prion conformers differ in their capacity to penetrate the CNS; certain fibrillar prions replicate persistently in lymphoid tissues with no CNS entry, leading to chronic silent carriers. Subclinical carriers of variant Creutzfeldt-Jakob (vCJD) prions in the United Kingdom have been estimated at 1:2000, and vCJD prions have been transmitted through blood transfusion, however, the circulating prion conformers that neuroinvade remain unclear. Here we investigate how prion conformation impacts brain entry of transfused prions by challenging mice intravenously to subfibrillar and fibrillar strains. We show that most strains infiltrated the brain and caused terminal disease, however, the fibrillar prions showed reduced CNS entry in a strain-dependent manner. Strikingly, the highly fibrillar mCWD prion strain replicated in the spleen and emerged in the brain as a novel strain, indicating that a new neuroinvasive prion had been generated from a previously non-neuroinvasive strain. The new strain showed altered plaque morphology, brain regions targeted and biochemical properties and these properties were maintained upon intracerebral passage. Intracerebral passage of prion-infected spleen re-created the new strain. Splenic prions resembled the new strain biochemically and intracerebral passage of prion-infected spleen re-created the new strain, collectively suggesting splenic prion replication as a potential source. Taken together, these results indicate that intravenous exposure to prion-contaminated blood or blood products may generate novel neuroinvasive prion conformers and disease phenotypes, potentially arising from prion replication in non-neural tissues or from conformer selection.

  • 2.
    Aguilar-Calvo, Patricia
    et al.
    Univ Calif San Diego, CA 92093 USA; Pfizer, CA USA.
    Malik, Adela
    Univ Calif San Diego, CA 92093 USA; Fate Therapeut, CA USA.
    Sandoval, Daniel R.
    Univ Calif San Diego, CA USA; GSK plc, PA USA.
    Barback, Christopher
    Univ Calif San Diego, CA USA; Univ Colorado, CO USA.
    Orru, Christina D.
    NIAID, MT USA.
    Standke, Heidi G.
    Case Western Reserve Univ, OH USA.
    Thomas, Olivia R.
    Case Western Reserve Univ, OH USA.
    Dwyer, Chrissa A.
    Univ Calif San Diego, CA USA.
    Pizzo, Donald P.
    Univ Calif San Diego, CA 92093 USA.
    Bapat, Jaidev
    Univ Calif San Diego, CA 92093 USA.
    Soldau, Katrin
    Univ Calif San Diego, CA 92093 USA.
    Ogawa, Ryotaro
    Univ Calif San Diego, CA USA.
    Riley, Mckenzie B.
    Univ Alabama Birmingham, AL USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kraus, Allison
    Case Western Reserve Univ, OH USA.
    Caughey, Byron
    NIAID, MT USA.
    Iliff, Jeffrey J.
    VA Puget Sound Hlth Care Syst, WA USA; Univ Washington, WA USA.
    Vera, David R.
    Univ Calif San Diego, CA USA.
    Esko, Jeffrey D.
    Univ Calif San Diego, CA USA.
    Sigurdson, Christina J.
    Univ Calif San Diego, CA 92093 USA; UC San Diego Hlth, CA 92093 USA; Bristol Myers Squibb, CA USA.
    Neuronal Ndst1 depletion accelerates prion protein clearance and slows neurodegeneration in prion infection2023In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 19, no 9, article id e1011487Article in journal (Refereed)
    Abstract [en]

    Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a major extracellular matrix component. HS facilitates fibril formation in vitro, yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for accelerating prion conversion in vitro. Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase / N-sulfotransferase), from neurons or astrocytes, we then investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, only affecting mice infected with extracellular, plaque-forming, but not membrane bound, prions. Live PET imaging revealed rapid clearance of recombinant prion protein monomers into the CSF of mice expressing unsulfated HS, further suggesting that HS sulfate groups hinder transit of extracellular prion protein monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme to target to facilitate aggregate clearance. Prions cause a rapidly progressive neurologic disease and death with no curative treatment available. Prion aggregates accumulate exponentially in the brain of affected individuals triggering neuronal loss and neuroinflammation, yet the molecules that facilitate prion protein aggregation are largely unknown. We have found that prions in the brain preferentially bind to a highly sulfated endogenous polysaccharide, known as heparan sulfate (HS). Here we use genetically modified mice that express poorly sulfated, neuron-derived HS, and infect mice with different prions strains. We find that mice infected with a plaque-forming prion strain show a prolonged survival and fewer plaques compared to controls. We also found that recombinant prion protein was efficiently transported within the interstitial fluid of mice having poorly sulfated HS, suggesting more efficient clearance from the brain. Our study provides insight into how HS retains prion aggregates in the brain to accelerate disease and indicates a specific HS biosynthetic enzyme to target to enhance protein clearance.

  • 3.
    Aguilar-Calvo, Patricia
    et al.
    Univ Calif, CA 92093 USA.
    Sevillano, Alejandro M.
    Univ Calif, CA 92093 USA.
    Bapat, Jaidev
    Univ Calif, CA 92093 USA.
    Soldau, Katrin
    Univ Calif, CA 92093 USA.
    Sandoval, Daniel R.
    Univ Calif, CA USA.
    Altmeppen, Hermann C.
    Univ Med Ctr Hamburg, Germany.
    Linsenmeier, Luise
    Univ Med Ctr Hamburg, Germany.
    Pizzo, Donald P.
    Univ Calif, CA 92093 USA.
    Geschwind, Michael D.
    Univ Calif San Francisco, CA USA.
    Sanchez, Henry
    Univ Calif San Francisco, CA USA.
    Appleby, Brian S.
    Case w Reserve Univ, OH USA.
    Cohen, Mark L.
    Case w Reserve Univ, OH USA.
    Safar, Jiri G.
    Case w Reserve Univ, OH USA.
    Edland, Steven D.
    Univ Calif, CA USA.
    Glatzel, Markus
    Univ Med Ctr Hamburg, Germany.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Esko, Jeffrey D.
    Univ Calif, CA USA.
    Sigurdson, Christina J.
    Univ Calif, CA USA.
    Shortening heparan sulfate chains prolongs survival and reduces parenchymal plaques in prion disease caused by mobile, ADAM10-cleaved prions2020In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 139, no 3, p. 527-546Article in journal (Refereed)
    Abstract [en]

    Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1(+/-)) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography-mass spectrometry (LC-MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC-MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.

  • 4.
    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, 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.

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  • 5.
    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.

  • 6.
    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.

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  • 7.
    Arja, Katriann
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Elgland, Mathias
    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.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lindgren, Mikael
    Department of Physics, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Synthesis and Characterization of Novel Fluoro-glycosylated Porphyrins that can be Utilized as Theranostic Agents2018In: ChemistryOpen, ISSN 2191-1363, Vol. 7, no 7, p. 495-503Article in journal (Refereed)
    Abstract [en]

    Small molecules with modalities for a variety of imaging techniques as well as therapeutic activity are essential, as such molecules render opportunities to simultaneously conduct diagnosis and targeted therapy, so called theranostics. In this regard, glycoporphyrins have proven useful as theranostic agents towards cancer, as well as noncancerous conditions. Herein, the synthesis and characterization of heterobifunctional glycoconjugated porphyrins with two different sugar moieties, a common monosaccharide at three sites, and a 2-fluoro-2-deoxy glucose (FDG) moiety at the fourth site are presented. The fluoro-glycoconjugated porphyrins exhibit properties for multimodal imaging and photodynamic therapy, as well as specificity towards cancer cells. We foresee that our findings might aid in the chemical design of heterobifunctional glycoconjugated porphyrins that could be utilized as theranostic agents.

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  • 8.
    Arja, Katriann
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Elgland, Mathias
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Synthesis and Characterization of Oligothiophene-Porphyrin-Based Molecules That Can Be Utilized for Optical Assignment of Aggregated Amyloid-beta Morphotypes2018In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 6, article id 391Article in journal (Refereed)
    Abstract [en]

    Molecular tools for fluorescent imaging of protein aggregates are essential for understanding the significance of these pathological hallmarks in proteopathic neurodegenerative diseases, such as Alzheimers disease. Here, we report the synthesis of a series of oligothiophene porphyrin hybrids, OTPHs, and the evaluation of these dyes for fluorescent imaging of beta-amyloid aggregates in tissue sections from a transgenic mouse model with Alzheimers disease pathology. The OTPHs proved to be successful for spectral and lifetime imaging assessment of protein deposits and our findings confirm that the enhanced spectral range and distinct lifetime diversity of these novel tools allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye. In addition, the chemical identity of the porphyrin moiety, as well as the spacing between the two optical active moieties, influenced the OTPHs performance for fluorescent assignment of the protein deposits. We foresee that our findings will aid in the chemical design of dyes that can be utilized as optical tools for studying the polymorphic nature of protein aggregates associated with proteopathic neurodegenerative diseases.

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  • 9.
    Arja, Katriann
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Selegård, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Paloncyova, Marketa
    KTH Royal Inst Technol, Sweden; Palacky Univ Olomouc, Czech Republic.
    Linares, Mathieu
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Lindgren, Mikael
    Norwegian Univ Sci & Technol, Norway.
    Norman, Patrick
    KTH Royal Inst Technol, Sweden.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Self-Assembly of Chiro-Optical Materials from Nonchiral Oligothiophene-Porphyrin Derivatives and Random Coil Synthetic Peptides2023In: ChemPlusChem, E-ISSN 2192-6506, Vol. 88, no 1Article in journal (Refereed)
    Abstract [en]

    Biomimetic chiral optoelectronic materials can be utilized in electronic devices, biosensors and artificial enzymes. Herein, this work reports the chiro-optical properties and architectural arrangement of optoelectronic materials generated from self-assembly of initially nonchiral oligothiophene-porphyrin derivatives and random coil synthetic peptides. The photo-physical- and structural properties of the materials were assessed by absorption-, fluorescence- and circular dichroism spectroscopy, as well as dynamic light scattering, scanning electron microscopy and theoretical calculations. The materials display a three-dimensional ordered helical structure and optical activity that are observed due to an induced chirality of the optoelectronic element upon interaction with the peptide. Both these properties are influenced by the chemical composition of the oligothiophene-porphyrin derivative, as well as the peptide sequence. We foresee that our findings will aid in developing self-assembled optoelectronic materials with dynamic architectonical accuracies, as well as offer the possibility to generate the next generation of materials for a variety of bioelectronic applications.

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  • 10.
    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.

  • 11.
    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.

  • 12.
    Bednarska, Natalia G.
    et al.
    KULeuven, Belgium; VIB, Belgium.
    van Eldere, Johan
    KULeuven, Belgium.
    Gallardo, Rodrigo
    VIB, Belgium; KULeuven, Belgium.
    Ganesan, Ashok
    VIB, Belgium; KULeuven, Belgium.
    Ramakers, Meine
    VIB, Belgium; KULeuven, Belgium.
    Vogel, Isabel
    KULeuven, Belgium.
    Baatsen, Pieter
    VIB11, Belgium; KULeuven, Belgium.
    Staes, An
    VIB, Belgium; University of Ghent, Belgium.
    Goethals, Marc
    VIB, Belgium; University of Ghent, 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.
    Gevaert, Kris
    VIB, Belgium; University of Ghent, Belgium.
    Schymkowitz, Joost
    VIB, Belgium; KULeuven, Belgium.
    Rousseau, Frederic
    VIB, Belgium; KULeuven, Belgium.
    Protein aggregation as an antibiotic design strategy2016In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 99, no 5, p. 849-865Article in journal (Refereed)
    Abstract [en]

    Taking advantage of the xenobiotic nature of bacterial infections, we tested whether the cytotoxicity of protein aggregation can be targeted to bacterial pathogens without affecting their mammalian hosts. In particular, we examined if peptides encoding aggregation-prone sequence segments of bacterial proteins can display antimicrobial activity by initiating toxic protein aggregation in bacteria, but not in mammalian cells. Unbiased in vitro screening of aggregating peptide sequences from bacterial genomes lead to the identification of several peptides that are strongly bactericidal against methicillin-resistant Staphylococcus aureus. Upon parenteral administration in vivo, the peptides cured mice from bacterial sepsis without apparent toxic side effects as judged from histological and hematological evaluation. We found that the peptides enter and accumulate in the bacterial cytosol where they cause aggregation of bacterial polypeptides. Although the precise chain of events that leads to cell death remains to be elucidated, the ability to tap into aggregation-prone sequences of bacterial proteomes to elicit antimicrobial activity represents a rich and unexplored chemical space to be mined in search of novel therapeutic strategies to fight infectious diseases.

  • 13.
    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.

  • 14.
    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.

  • 15.
    Bergkvist, Liza
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Richards, Daniel R.
    Univ Cambridge, England.
    Bernardo-Gancedo, Ana
    Univ Cambridge, England.
    Kumita, Janet R.
    Univ Cambridge, England.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Serum amyloid P component promotes formation of distinct aggregated lysozyme morphologies and reduces toxicity in Drosophila flies expressing F57I lysozyme2020In: PLOS ONE, E-ISSN 1932-6203, Vol. 15, no 1, article id e0227227Article in journal (Refereed)
    Abstract [en]

    Many conflicting reports about the involvement of serum amyloid P component (SAP) in amyloid diseases have been presented over the years; SAP is known to be a universal component of amyloid aggregates but it has been suggested that it can both induce and suppress amyloid formation. By using our Drosophila model of systemic lysozyme amyloidosis, SAP has previously been shown to reduce the toxicity induced by the expression of the disease-associated lysozyme variant, F57I, in the Drosophila central nervous system. This study further investigates the involvement of SAP in modulating lysozyme toxicity using histochemistry and spectral analyses on the double transgenic WT and F57I lysozyme flies to probe; i) formation of aggregates, ii) morphological differences of the aggregated lysozyme species formed in the presence or absence of SAP, iii) location of lysozyme and iv) co-localisation of lysozyme and SAP in the fly brain. We found that SAP can counteract the toxicity (measured by the reduction in the median survival time) induced by F57I lysozyme by converting toxic F57I species into less toxic amyloid-like structures, as reflected by the spectral changes that p-FTAA undergoes when bound to lysozyme deposits in F57I-F57I-SAP flies as compared to F57I-F57I flies. Indeed, when SAP was introduced to in vitro lysozyme fibril formation, the endpoint fibrils had enhanced ThT fluorescence intensity as compared to lysozyme fibrils alone. This suggests that a general mechanism for SAPs role in amyloid diseases may be to promote the formation of stable, amyloid-like fibrils, thus decreasing the impact of toxic species formed along the aggregation pathway.

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  • 16.
    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.

  • 17.
    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.

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  • 18.
    Björk, Linnea
    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.
    Ghetti, Bernardino
    Indiana Univ Sch Med, IN 46202 USA.
    Vidal, Ruben
    Indiana Univ Sch Med, IN 46202 USA.
    Klingstedt, Therése
    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.
    Proteophenes - Amino Acid Functionalized Thiophene-based Fluorescent Ligands for Visualization of Protein Deposits in Tissue Sections with Alzheimers Disease Pathology2022In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 28, no 62, article id e202201557Article in journal (Refereed)
    Abstract [en]

    Protein deposits composed of specific proteins or peptides are associated with several neurodegenerative diseases and fluorescent ligands able to detect these pathological hallmarks are vital. Here, we report the synthesis of a class of thiophene-based ligands, denoted proteophenes, with different amino acid side-chain functionalities along the conjugated backbone, which display selectivity towards specific disease-associated protein aggregates in tissue sections with Alzheimers disease (AD) pathology. The selectivity of the ligands towards AD associated pathological hallmarks, such as aggregates of the amyloid-beta (A beta) peptide or tau filamentous inclusions, was highly dependent on the chemical nature of the amino acid functionality, as well as on the location of the functionality along the pentameric thiophene backbone. Finally, the concept of synthesizing donor-acceptor-donor proteophenes with distinct photophysical properties was shown. Our findings provide the structural and functional basis for the development of new thiophene-based ligands that can be utilized for optical assignment of different aggregated proteinaceous species in tissue sections.

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  • 19.
    Björk, Linnea
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Thiophene-Based Ligands: Design, Synthesis and Their Utilization for Optical Assignment of Polymorphic-Disease-Associated Protein Aggregates2023In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 24, article id e202300044Article, review/survey (Refereed)
    Abstract [en]

    The development of ligands for detecting protein aggregates is of great interest, as these aggregated proteinaceous species are the pathological hallmarks of several devastating diseases, including Alzheimers disease. In this regard, thiophene-based ligands have emerged as powerful tools for fluorescent assessment of these pathological entities. The intrinsic conformationally sensitive photophysical properties of poly- and oligothiophenes have allowed optical assignment of disease-associated protein aggregates in tissue sections, as well as real-time in vivo imaging of protein deposits. Herein, we recount the chemical evolution of different generations of thiophene-based ligands, and exemplify their use for the optical distinction of polymorphic protein aggregates. Furthermore, the chemical determinants for achieving a superior fluorescent thiophene-based ligand, as well as the next generation of thiophene-based ligands targeting distinct aggregated species are described. Finally, the directions for future research into the chemical design of thiophene-based ligands that can aid in resolving the scientific challenges around protein aggregation diseases are discussed.

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  • 20.
    Björk, Linnea
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Selegård, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Bäck, Marcus
    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.
    Lindgren, Mikael
    Norwegian Univ Sci & Technol, Norway.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Amino-Acid Side-Chain Nanoarchitectonics for Tuning the Chiroptical Properties and Supramolecular Structure of Pentameric Oligothiophenes2024In: ChemPhotoChem, E-ISSN 2367-0932Article in journal (Refereed)
    Abstract [en]

    Oligothiophenes with specific photophysical properties and molecular organization are of great interest, since this class of materials are used in organic electronics and bioelectronics, as well as biosensing. Herein, 8 different pentameric oligothiophenes, denoted proteophenes, with different amino acid substitution patterns at distinct positions along the thiophene backbone were investigated. Spectroscopic and microscopic studies of the ligands revealed the formation of optically active self-assembled materials under acidic or basic conditions. The distinct photophysical characteristics, including induced circular dichroism, as well as the supramolecular structures of the assemblies deduced from light scattering and transmission electron microscopy, were highly influenced by the positioning of distinct amino acid moieties along the thiophene backbone. Proteophenes functionalized with only glutamate residues or these functionalities in combination with hydrophobic valine moieties formed fibrillar structures with excellent chiroptical properties under acidic conditions. In addition, the amino acid functionality at the beta-position of distinct thiophene moieties influenced the induced circular dichroism pattern observed from the proteophenes. Overall, the obtained results demonstrate how changes in the position of various amino acid functionalities, as well as the chemical nature of the amino acid side chain functionality greatly affect the optical properties as well as the architecture of the self-assembled materials. Self-assembled Proteophenes. Oligothiophenes with distinct amino acid side-chain functionalities along the conjugated backbone displayed distinct chiroptical and structural properties in acidic or alkaline solutions. The distinct photophysical characteristics, as well as the supramolecular structures of the assemblies were highly influenced by the chemical nature of the amino acid, as well as the positioning of distinct amino acid moieties along the thiophene backbone.image

  • 21.
    Björk, Linnea
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Todarwal, Yogesh
    KTH Royal Inst Technol, Sweden.
    Linares, Mathieu
    KTH Royal Inst Technol, Sweden.
    Vidal, Ruben
    Indiana Univ Sch Med, IN 46202 USA.
    Ghetti, Bernardino
    Indiana Univ Sch Med, IN 46202 USA.
    Norman, Patrick
    KTH Royal Inst Technol, Sweden.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, K. Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Distinct Heterocyclic Moieties Govern the Selectivity of Thiophene-Vinylene-Based Ligands towards Aß or Tau Pathology in Alzheimer's Disease2023In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, article id e202300583Article in journal (Refereed)
    Abstract [en]

    Distinct aggregated proteins are correlated with numerous neurodegenerative diseases and the development of ligands that selectively detect these pathological hallmarks is vital. Recently, the synthesis of thiophene-based optical ligands, denoted bi-thiophene-vinyl-benzothiazoles (bTVBTs), that could be utilized for selective assignment of tau pathology in brain tissue with Alzheimers disease (AD) pathology, was reported. Herein, we investigate the ability of these ligands to selectively distinguish tau deposits from aggregated amyloid-beta (A beta), the second AD associated pathological hallmark, when replacing the terminal thiophene moiety with other heterocyclic motifs. The selectivity for tau pathology was reduced when introducing specific heterocyclic motifs, verifying that specific molecular interactions between the ligands and the aggregates are necessary for selective detection of tau deposits. In addition, ligands having certain heterocyclic moieties attached to the central thiophene-vinylene building block displayed selectivity to aggregated A beta pathology. Our findings provide chemical insights for the development of ligands that can distinguish between aggregated proteinaceous species consisting of different proteins and might also aid in creating novel agents for clinical imaging of tau pathology in AD.

  • 22.
    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.

  • 23.
    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.

  • 24.
    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.

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  • 25.
    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.

  • 26.
    Butina, Karen
    et al.
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Lantz, Linda
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Choong, Ferdinand X.
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Tomac, Ana
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Löffler, Susanne
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden.
    Richter-Dahlfors, Agneta
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Structural Properties Dictating Selective Optotracer Detection of Staphylococcus aureus2022In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 23, no 11, article id e202100684Article in journal (Refereed)
    Abstract [en]

    Optotracers are conformation-sensitive fluorescent tracer molecules that detect peptide- and carbohydrate-based biopolymers. Their binding to bacterial cell walls allows selective detection and visualisation of Staphylococcus aureus (S. aureus). Here, we investigated the structural properties providing optimal detection of S. aureus. We quantified spectral shifts and fluorescence intensity in mixes of bacteria and optotracers, using automatic peak analysis, cross-correlation, and area-under-curve analysis. We found that the length of the conjugated backbone and the number of charged groups, but not their distribution, are important factors for selective detection of S. aureus. The photophysical properties of optotracers were greatly improved by incorporating a donor-acceptor-donor (D-A-D)-type motif in the conjugated backbone. With significantly reduced background and binding-induced on-switch of fluorescence, these optotracers enabled real-time recordings of S. aureus growth. Collectively, this demonstrates that chemical structure and photophysics are key tunable characteristics in the development of optotracers for selective detection of bacterial species.

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  • 27.
    Butina, Karen
    et al.
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Tomac, Ana
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Choong, Ferdinand X.
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Shirani, Hamid
    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. Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden.
    Loffler, Susanne
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Richter-Dahlfors, Agneta
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Optotracing for selective fluorescence-based detection, visualization and quantification of liveS. aureusin real-time2020In: npj Biofilms and Microbiomes, E-ISSN 2055-5008, Vol. 6, no 1, article id 35Article in journal (Refereed)
    Abstract [en]

    Methods for bacterial detection are needed to advance the infection research and diagnostics. Based on conformation-sensitive fluorescent tracer molecules, optotracing was recently established for dynamic detection and visualization of structural amyloids and polysaccharides in the biofilm matrix of gram-negative bacteria. Here, we extend the use of optotracing for detection of gram-positive bacteria, focussing on the clinically relevant opportunistic human pathogenStaphylococcus aureus. We identify a donor-acceptor-donor-type optotracer, whose binding-induced fluorescence enables real-time detection, quantification, and visualization ofS. aureusin monoculture and when mixed with gram-negativeSalmonellaEnteritidis. An algorithm-based automated high-throughput screen of 1920S. aureustransposon mutants recognized the cell envelope as the binding target, which was corroborated by super-resolution microscopy of bacterial cells and spectroscopic analysis of purified cell wall components. The binding event was essentially governed by hydrophobic interactions, which permitted custom-designed tuning of the binding selectivity towardsS. aureusversusEnterococcus faecalisby appropriate selection of buffer conditions. Collectively this work demonstrates optotracing as an enabling technology relevant for any field of basic and applied research, where visualization and detection ofS. aureusis needed.

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  • 28.
    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.

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  • 29.
    Bäck, Marcus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Selegård, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Todarwal, Yogesh
    KTH Royal Inst Technol, Sweden.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Norman, Patrick
    KTH Royal Inst Technol, Sweden.
    Linares, Mathieu
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Norwegian Univ Sci & Technol, Norway.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Tyrosine Side-Chain Functionalities at Distinct Positions Determine the Chirooptical Properties and Supramolecular Structures of Pentameric Oligothiophenes2020In: ChemistryOpen, ISSN 2191-1363, Vol. 9, no 11, p. 1100-1108Article in journal (Refereed)
    Abstract [en]

    Control over the photophysical properties and molecular organization of pi-conjugated oligothiophenes is essential to their use in organic electronics. Herein we synthesized and characterized a variety of anionic pentameric oligothiophenes with different substitution patterns of L- or D-tyrosine at distinct positions along the thiophene backbone. Spectroscopic, microscopic, and theoretical studies of L- or D-tyrosine substituted pentameric oligothiophene conjugates revealed the formation of optically active pi-stacked self-assembled aggregates under acid conditions. The distinct photophysical characteristics, as well as the supramolecular structures of the assemblies, were highly influenced by the positioning of the L- or D-tyrosine moieties along the thiophene backbone. Overall, the obtained results clearly demonstrate how fundamental changes in the position of the enantiomeric side-chain functionalities greatly affect the optical properties as well as the architecture of the self-assembled supramolecular structures.

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  • 30.
    Calvo-Rodriguez, Maria
    et al.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Hou, Steven S.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Snyder, Austin C.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Dujardin, Simon
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Shirani, Hamid
    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.
    Bacskai, Brian J.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    In vivo detection of tau fibrils and amyloid beta aggregates with luminescent conjugated oligothiophenes and multiphoton microscopy2019In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 7, no 1, article id 171Article in journal (Refereed)
    Abstract [en]

    The detection of amyloid beta deposits and neurofibrillary tangles, both hallmarks of Alzheimers disease (AD), is key to understanding the mechanisms underlying these pathologies. Luminescent conjugated oligothiophenes (LCOs) enable fluorescence imaging of these protein aggregates. Using LCOs and multiphoton microscopy, individual tangles and amyloid beta deposits were labeled in vivo and imaged longitudinally in a mouse model of tauopathy and cerebral amyloidosis, respectively. Importantly, LCO HS-84, whose emission falls in the green region of the spectrum, allowed for the first time longitudinal imaging of tangle dynamics following a single intravenous injection. In addition, LCO HS-169, whose emission falls in the red region of the spectrum, successfully labeled amyloid beta deposits, allowing multiplexing with other reporters whose emission falls in the green region of the spectrum. In conclusion, this method can provide a new approach for longitudinal in vivo imaging using multiphoton microscopy of AD pathologies as well as other neurodegenerative diseases associated with protein aggregation in mouse models.

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  • 31.
    Calvo-Rodriguez, Maria
    et al.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA; AbbVie Inc, MA USA.
    Kharitonova, Elizabeth K.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Snyder, Austin C.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Hou, Steven S.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Sanchez-Mico, Maria Virtudes
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Das, Sudeshna
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Fan, Zhanyun
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Shirani, Hamid
    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.
    Serrano-Pozo, Alberto
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Bacskai, Brian J.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid ß aggregates in vivo in a mouse model of Alzheimer's disease2024In: Molecular Neurodegeneration, E-ISSN 1750-1326, Vol. 19, no 1, article id 6Article in journal (Refereed)
    Abstract [en]

    BackgroundReactive oxidative stress is a critical player in the amyloid beta (A beta) toxicity that contributes to neurodegeneration in Alzheimer's disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in A beta plaque-associated dystrophic neurites in the AD brain. Although A beta causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether A beta plaques and soluble A beta oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants.MethodsWe expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease and performed intravital multiphoton microscopy of neuronal mitochondria and A beta plaques.ResultsFor the first time, we demonstrated by direct observation in the living mouse brain exacerbated mitochondrial oxidative stress in neurons after both A beta plaque deposition and direct application of soluble oligomeric A beta onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31. Remarkably, the latter ameliorated plaque-associated dystrophic neurites without impacting A beta plaque burden.ConclusionsConsidering these results, combination of mitochondria-targeted compounds with other anti-amyloid beta or anti-tau therapies hold promise as neuroprotective drugs for the prevention and/or treatment of AD.

  • 32.
    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, 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.

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  • 33.
    Choong, Ferdinand
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Fahlen, Sara
    Karolinska Institutet, Stockholm, Sweden.
    Johansson, Leif B. G.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Melican, Keira
    Karolinska Institutet, Stockholm, Sweden.
    Rhen, Mikael
    Karolinska Institutet, Stockholm, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Richter-Dahlfors, Agneta
    Karolinska Institutet, Stockholm, Sweden.
    Real-time opto-tracing of curli and cellulose in live Salmonella biofilms using conjugated oligothiophenes2016In: npj Biofilms and Microbiomes, E-ISSN 2055-5008, Vol. 2, article id 16024Article in journal (Refereed)
    Abstract [en]

    Extracellular matrix (ECM) is the protein- and polysaccharide-rich backbone of bacterial biofilms that provides a defensive barrier in clinical, environmental and industrial settings. Understanding the dynamics of biofilm formation in native environments has been hindered by a lack of research tools. Here we report a method for simultaneous, real-time, in situ detection and differentiation of the Salmonella ECM components curli and cellulose, using non-toxic, luminescent conjugated oligothiophenes (LCOs). These flexible conjugated polymers emit a conformation-dependent fluorescence spectrum, which we use to kinetically define extracellular appearance of curli fibres and cellulose polysaccharides during bacterial growth. The scope of this technique is demonstrated by defining biofilm morphotypes of Salmonella enterica serovars Enteritidis and Typhimurium, and their isogenic mutants in liquid culture and on solid media, and by visualising the ECM components in native biofilms. Our reported use of LCOs across a number of platforms, including intracellular cellulose production in eukaryotic cells and in infected tissues, demonstrates the versatility of this optotracing technology, and its ability to redefine biofilm research.

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  • 34.
    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, 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.

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  • 35.
    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, 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.

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  • 36.
    Choong, Ferdinand X.
    et al.
    Karolinska Inst, Sweden.
    Lantz, Linda
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Shirani, Hamid
    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 a donor-acceptor-donor conjugated pentamer enables multi-carbohydrate anatomical mapping in plant tissues2019In: Cellulose, ISSN 0969-0239, E-ISSN 1572-882X, Vol. 26, no 7, p. 4253-4264Article in journal (Refereed)
    Abstract [en]

    Optotracing is a novel method for analytical imaging of carbohydrates in plant and microbial tissues. This optical method applies structure-responsive oligothiophenes as molecular fluorophores emitting unique optical signatures when bound to polysaccharides. Herein, we apply Carbotrace680, a short length anionic oligothiophene with a central heterocyclic benzodithiazole (BTD) motif, to probe for different glucans. The donor-acceptor-donor type electronic structure of Carbotrace680 provides improved spectral properties compared to oligothiophenes due to the possibility of intramolecular charge-transfer transition to the BTD motif. This enables differentiation of glucans based on the glycosidic linkage stereochemistry. Thus -configured starch is readily differentiated from -configured cellulose. The versatility of optotracing is demonstrated by dynamic monitoring of thermo-induced starch remodelling, shown in parallel by spectrophotometry and microscopy of starch granules. Imaging of Carbotrace680 bound to multiple glucans in plant tissues provided direct identification of their physical locations, revealing the spatial relationship between structural (cellulose) and storage (starch) glucans at sub-cellular scale. Our work forms the basis for the development of superior optotracers for sensitive detection of polysaccharides. Our non-destructive method for anatomical mapping of glucans in biomass will serve as an enabling technology for developments towards efficient use of plant-derived materials and biomass. [GRAPHICS] .

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  • 37.
    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, 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.

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  • 38.
    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.

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  • 39.
    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.

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  • 40.
    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.

  • 41.
    Faustini, Gaia
    et al.
    Univ Brescia, Italy.
    Longhena, Francesca
    Univ Brescia, Italy.
    Masato, Anna
    Univ Padua, Italy.
    Bassareo, Valentina
    Univ Cagliari, Italy.
    Frau, Roberto
    Univ Cagliari, Italy.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Brembati, Viviana
    Univ Brescia, Italy.
    Parrella, Edoardo
    Univ Brescia, Italy.
    Vezzoli, Marika
    Univ Brescia, Italy.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Pizzi, Marina
    Univ Brescia, Italy.
    Spillantini, Maria Grazia
    Univ Cambridge, England.
    Bubacco, Luigi
    Univ Padua, Italy.
    Bellucci, Arianna
    Univ Brescia, Italy.
    Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinsons disease-like phenotype2022In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 30, no 4, p. 1465-1483Article in journal (Refereed)
    Abstract [en]

    Fibrillary aggregated alpha-synuclein (alpha-syn) deposition in Lewy bodies (LB) characterizes Parkinsons disease (PD) and is believed to trigger dopaminergic synaptic failure and a retrograde terminal-to-cell body neuronal degeneration. We described that the neuronal phosphoprotein synapsin III (Syn III) cooperates with alpha-syn to regulate dopamine (DA) release and can be found in the insoluble alpha-syn fibrils composing LB. Moreover, we showed that a-syn aggregates deposition, and the associated onset of synaptic deficits and neuronal degeneration occurring following adeno-associated viral vectors-mediated overexpression of human alpha-syn in the nigrostriatal system are hindered in Syn III knock out mice. This supports that Syn III facilitates alpha-syn aggregation. Here, in an interventional experimental design, we found that by inducing the gene silencing of Syn III in human alpha-syn transgenic mice at PD-like stage with advanced alpha-syn aggregation and overt striatal synaptic failure, we could lower alpha-syn aggregates and striatal fibers loss. In parallel, we observed recovery from synaptic vesicles clumping, DA release failure, and motor functions impairment. This supports that Syn III consolidates alpha-syn aggregates, while its downregulation enables their reduction and redeems the PD-like phenotype. Strategies targeting Syn III could thus constitute a therapeutic option for PD.

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  • 42.
    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.

  • 43.
    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)
  • 44. 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.

  • 45.
    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.

  • 46.
    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.

  • 47.
    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.

  • 48.
    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, 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.

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  • 49.
    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.

  • 50.
    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.

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