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  • 101.
    Owenius, Rikard
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Jarl, Anngelica
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Carlsson, Uno
    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.
    GroEL-induced topological dislocation of a substrate protein β-sheet core: a solution EPR spin–spin distance study2010In: Journal of chemical biology, ISSN 1864-6158, E-ISSN 1864-6166, Vol. 3, no 3, p. 127-39Article in journal (Refereed)
    Abstract [en]

    The Hsp60-type chaperonin GroEL assists in the folding of the enzyme human carbonic anhydrase II (HCA II) and protects it from aggregation. This study was aimed to monitor conformational rearrangement of the substrate protein during the initial GroEL capture (in the absence of ATP) of the thermally unfolded HCA II molten-globule. Single- and double-cysteine mutants were specifically spin-labeled at a topological breakpoint in the β-sheet rich core of HCA II, where the dominating antiparallel β-sheet is broken and β-strands 6 and 7 are parallel. Electron paramagnetic resonance (EPR) was used to monitor the GroEL-induced structural changes in this region of HCA II during thermal denaturation. Both qualitative analysis of the EPR spectra and refined inter-residue distance calculations based on magnetic dipolar interaction show that the spin-labeled positions F147C and K213C are in proximity in the native state of HCA II at 20 °C (as close as ∼8 Å), and that this local structure is virtually intact in the thermally induced molten-globule state that binds to GroEL. In the absence of GroEL, the molten globule of HCA II irreversibly aggregates. In contrast, a substantial increase in spin–spin distance (up to >20 Å) was observed within minutes, upon interaction with GroEL (at 50 and 60 °C), which demonstrates a GroEL-induced conformational change in HCA II. The GroEL binding-induced disentanglement of the substrate protein core at the topological break-point is likely a key event for rearrangement of this potent aggregation initiation site, and hence, this conformational change averts HCA II misfolding.

  • 102. Persson, M
    et al.
    Zhou, A
    Mitri, R
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Carlsson, Uno
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Eaton, GR
    Eaton, SS
    Distance determination between deeply buried position in human carbon anhydrase II2000In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 78, no 1, p. 2255Pos-Conference paper (Other academic)
  • 103.
    Persson, Malin
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Lindgren, M.
    Jonsson, Bengt-Harald
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology .
    Svensson, Magdalena
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Carlsson, Uno
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    EPR Mapping of Interactions Between Spin-labeled Variants of Human Carbonic Anhydrase II and GroEL. Evidence for increased flexibility of the hydrophobic core by the interaction.1999In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 38, p. 432-441Article in journal (Refereed)
  • 104.
    Persson, Malin
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Harbridge, JR
    Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA Linkoping Univ, Dept Chem, IFM, SE-58183 Linkoping, Sweden.
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Mitri, R
    Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA Linkoping Univ, Dept Chem, IFM, SE-58183 Linkoping, Sweden.
    Mårtensson, Lars-Göran
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Carlsson, Uno
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Eaton, GR
    Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA Linkoping Univ, Dept Chem, IFM, SE-58183 Linkoping, Sweden.
    Eaton, SS
    Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA Linkoping Univ, Dept Chem, IFM, SE-58183 Linkoping, Sweden.
    Comparison of electron paramagnetic resonance methods to determine distances between spin labels on human carbonic anhydrase II2001In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 80, no 6, p. 2886-2897Article in journal (Refereed)
    Abstract [en]

    Four doubly spin-labeled variants of human carbonic anhydrase II and corresponding singly labeled variants were prepared by site-directed spin labeling. The distances between the spin labels were obtained from continuous-wave electron paramagnetic resonance spectra by analysis of the relative intensity of the half-field transition, Fourier deconvolution of line-shape broadening, and computer simulation of line-shape changes. Distances also were determined by four-pulse double electron-electron resonance. For each variant, at least two methods were applicable and reasonable agreement between methods was obtained. Distances ranged from 7 to 24 W. The doubly spin-labeled samples contained some singly labeled protein due to incomplete labeling. The sensitivity of each of the distance determination methods to the noninteracting component was compared.

  • 105.
    Philipson, O.
    et al.
    Uppsala University.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Portelius, E.
    Sahlgrenska University Hospital.
    Olofsson, T.
    Uppsala University.
    Ingelsson, M.
    Uppsala University.
    Hyman, B.T.
    Massachusetts General Hospital.
    Blennow, K.
    Sahlgrenska University Hospital.
    Lannfelt, L.
    Uppsala University.
    Kalimo, H.
    Uppsala University.
    Nilsson, L.N.G.
    Uppsala University.
    A highly insoluble state of Aβ similar to that of Alzheimers disease brain is found in Arctic APP transgenic mice2009In: Neurobiology of Aging, ISSN 0197-4580, Vol. 30, no 9, p. 1393-1405Article in journal (Refereed)
    Abstract [en]

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

  • 106.
    Psonka-Antonczyk, Katarzyna M.
    et al.
    Department of Physics, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Johansson, Leif
    Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Chemistry.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Department of Physics, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
    Stokke, Björn T.
    Department of Physics, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nanoscale Structure and Spectroscopic Probing of A beta 1-40 Fibril Bundle Formation2016In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 4, article id 44Article in journal (Refereed)
    Abstract [en]

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

  • 107.
    Rasmussen, Jay
    et al.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany; University of Tubingen, Germany.
    Mahler, Jasmin
    University of Tubingen, Germany.
    Beschorner, Natalie
    University of Tubingen, Germany.
    Kaeser, Stephan A.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Haesler, Lisa M.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Baumann, Frank
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Portelius, Erik
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Blennow, Kaj
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Lashley, Tammaryn
    UCL, England.
    Fox, Nick C.
    UCL, England.
    Sepulveda-Falla, Diego
    University of Medical Centre Hamburg Eppendorf, Germany; University of Antioquia, Colombia; University of Antioquia, Colombia.
    Glatzel, Markus
    University of Medical Centre Hamburg Eppendorf, Germany.
    Oblak, Adrian L.
    Indiana University of School Med, IN 46202 USA.
    Ghetti, Bernardino
    Indiana University of School Med, IN 46202 USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Staufenbiel, Matthias
    University of Tubingen, Germany.
    Walker, Lary C.
    Emory University, GA 30329 USA.
    Jucker, Mathias
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimers disease2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 49, p. 13018-13023Article in journal (Refereed)
    Abstract [en]

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

  • 108.
    Schuetz, Anne K.
    et al.
    Swiss Fed Inst Technol, Switzerland.
    Hornemann, Simone
    Univ Zurich, Switzerland.
    Waelti, Marielle A.
    Swiss Fed Inst Technol, Switzerland.
    Greuter, Ladina
    Univ Zurich, Switzerland.
    Tiberi, Cinzia
    Univ Zurich, Switzerland.
    Cadalbert, Riccardo
    Swiss Fed Inst Technol, Switzerland.
    Gantner, Matthias
    Swiss Fed Inst Technol, Switzerland.
    Riek, Roland
    Swiss Fed Inst Technol, Switzerland.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Boeckmann, Anja
    Univ Lyon 1, France.
    Aguzzi, Adriano
    Univ Zurich, Switzerland.
    Meier, Beat H.
    Swiss Fed Inst Technol, Switzerland.
    Binding of Polythiophenes to Amyloids: Structural Mapping of the Pharmacophore2018In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 9, no 3, p. 475-481Article in journal (Refereed)
    Abstract [en]

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

  • 109.
    Sekijima, Y
    et al.
    The Skaggs Institute of Chemical Biology.
    Wiseman, R.L.
    The Skaggs Institute of Chemical Biology.
    Matteson, J
    The Scripps Research Institute.
    Hammarström, Per
    The Skaggs Institute of Chemical Biology.
    Miller, S.R
    The Skaggs Institute of Chemical Biology.
    Balch, W.E
    The Scripps Research Institute.
    Kelly, J.W.
    The Skaggs Institute of Chemical Biology.
    The Biological and Chemical Basis for Tissue Selective Transthyretin Amyloid Disease2005In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 121, no 1, p. 73-85Article in journal (Refereed)
    Abstract [en]

    Factors controlling the onset and progression of extracellular amyloid diseases remain largely unknown. Central to disease etiology is the efficiency of the endoplasmic reticulum (ER) machinery that targets destabilized mutant proteins for degradation and the enhanced tendency of these variants to aggregate if secreted. We demonstrate that mammalian cells secrete numerous transthyretin (TTR) disease-associated variants with wild-type efficiency in spite of compromised folding energetics. Only the most highly destabilized TTR variants are subjected to ER-associated degradation (ERAD) and then only in certain tissues, providing insight into tissue selective amyloidosis. Rather than a quality control standard based on wild-type stability, we find that ER-assisted folding (ERAF), based on global protein energetics, determines the extent of export. We propose that ERAF (influenced by the energetics of the protein fold, chaperone enzyme distributions, and metabolite chaperones) in competition with ERAD defines the unique secretory aptitude of each tissue.

  • 110.
    Sekijima, Yoshiki
    et al.
    Shinshu University,Matsumoto, Japan.
    Campos, Raul Ivan
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Yoshinaga, Tsuneaki
    Shinshu University, Matsumoto, Japan.
    Nagamatsu, Kiyoshiro
    Shinshu University, Matsumoto, Japan.
    Yazaki, Masahide
    Shinshu University,Matsumoto, Japan.
    Kametani, Fuyuki
    Tokyo Metropolitan Org Medical Research, Japan.
    Ikeda, Shu-ichi
    Shinshu University, Matsumoto, Japan.
    Pathological, biochemical, and biophysical characteristics of the transthyretin variant Y114H (p.Y134H) explain its very mild clinical phenotype2015In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 20, no 4, p. 372-379Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 112.
    Sjöberg, Andreas P.
    et al.
    Lund University, Department of Laboratory Medicine, Division of Medical Protein Chemistry, Wallenberg Laboratory, Malmö, Sweden.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Blom, Anna M.
    Lund University, Department of Laboratory Medicine, Division of Medical Protein Chemistry, Wallenberg Laboratory, Malmö, Sweden.
    Native, amyloid fibrils and β-oligomers of the C-terminal domain of human prion protein display differential activation of complement and bind C1q, factor H and C4b-binding protein directly2008In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 45, no 11, p. 3213-3221Article in journal (Refereed)
    Abstract [en]

    Prion protein (PrP) is an endogenous protein involved in the pathogenesis of bovine spongiform encephalopathy and Creutzfeldt–Jakob disease. Murine PrP has been reported to bind C1q and activate the classical pathway of complement in a copper-dependent manner. Here we show that various conformational isoforms (native, amyloid fibrils, and β-oligomers) of recombinant human PrP (90–231 and 121–231) bind C1q and activate complement. PrP binds both the globular head and collagenous stalk domains of C1q. Native, β-oligomeric and amyloid fibrils of PrP all activate the classical and alternative pathways of complement to different extent. However, they do not trigger the lectin pathway. Of the tested PrP conformational isoforms we find that β-oligomers bind C1q and activate complement most strongly. Membrane attack complex formation initiated by PrP is subdued in comparison to deposition of early complement components. This is most likely attributed to the interaction between human PrP and complement inhibitors factor H and C4b-binding protein. Accordingly, PrP-triggered complement activation in the terminal pathway was increased in serum lacking C4b-binding protein. Taken together the present study indicates that complement activation may be an important factor in human prion diseases, suggesting that complement induced activities may prove relevant therapeutic targets.

  • 113.
    Sjölander, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Bijzet, Johan
    Department of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
    Hazenberg, Bouke P.
    Department of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Sensitive and rapid assessment of amyloid by oligothiophene fluorescence in subcutaneous fat tissue2015In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 22, no 1, p. 19-25Article in journal (Refereed)
    Abstract [en]

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

  • 114.
    Sjölander, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Mason, Jeffrey
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Westermark, G. T.
    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Westermark, P.
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Luminescent conjugated oligothiophenes: A novel dye for amyloid diagnostics2013In: XIIIth International Symposium on Amyloidosis: From Misfolded Proteins to Well-Designed Treatment: The Proceedings of the XIIIth International Symposium on Amyloidosis,May 6-10, 2012, Groningen, The Netherlands / [ed] Bouke P.C. Hazenberg and Johan Bijzet, GUARD (Groningen Unit for Amyloidosis Research & Development) , 2013, p. 179-182Conference paper (Refereed)
    Abstract [en]

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

  • 115.
    Sjölander, Daniel
    et al.
    Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Chemistry.
    Roecken, Christoph
    University of Kiel, Germany.
    Westermark, Per
    Uppsala University, Sweden.
    Westermark, Gunilla T.
    Uppsala University, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Establishing the fluorescent amyloid ligand h-FTAA for studying human tissues with systemic and localized amyloid2016In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 23, no 2, p. 98-108Article in journal (Refereed)
    Abstract [en]

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

  • 116.
    Sjölander, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Röcken, Christoph
    Institute of Pathology, Christian-Albrechts-Univeristy, Kiel, Germany.
    Westermark, Per
    Department of Immunology, Uppsala University, Uppsala, Sweden.
    Westermark, Gunilla T.
    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Evaluation of the fluorescent amyloid ligand h-FTAA in human tissues with systemic and localized amyloid2014Manuscript (preprint) (Other academic)
    Abstract [en]

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

  • 117.
    Sole-Domenech, Santiago
    et al.
    Karolinska Institute, Sweden .
    Sjovall, Peter
    SP Technical Research Institute Sweden, Sweden .
    Vukojevic, Vladana
    Karolinska Institute, Sweden .
    Fernando, Ruani
    Hop St Eloi, France .
    Codita, Alina
    Karolinska Institute, Sweden .
    Salve, Sachin
    Karolinska Institute, Sweden .
    Bogdanovic, Nenad
    Karolinska Institute, Sweden .
    H Mohammed, Abdul
    Karolinska Institute, Sweden .
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    M LaFerla, Frank
    University of Calif Irvine, CA USA .
    Jacob, Stefan
    Karolinska Institute, Sweden .
    Berggren, Per-Olof
    Karolinska Institute, Sweden .
    Gimenez-Llort, Lydia
    University of Autonoma Barcelona, Spain .
    Schalling, Martin
    Karolinska Institute, Sweden .
    Terenius, Lars
    Karolinska Institute, Sweden .
    Johansson, Bjorn
    Karolinska Institute, Sweden .
    Localization of cholesterol, amyloid and glia in Alzheimers disease transgenic mouse brain tissue using time-of-flight secondary ion mass spectrometry (ToF-SIMS) and immunofluorescence imaging2013In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 125, no 1, p. 145-157Article in journal (Refereed)
    Abstract [en]

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

  • 118.
    Sörgjerd, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Ghafouri, Bijar
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine . Linköping University, Faculty of Health Sciences.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Kelly, Jeffery W.
    The Skaggs Institute of Chemical Biology and the Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
    Blond, Sylvie Y.
    Center for Pharmaceutical Biotechnology, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, IL, USA .
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Retention of Misfolded Mutant Transthyretin by the Chaperone BiP/GRP78 Mitigates Amyloidogenesi2006In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 356, no 2, p. 469-482 Article in journal (Refereed)
    Abstract [en]

    Carriers of the D18G transthyretin (TTR) mutation display an unusual central nervous system (CNS) phenotype with late onset of disease. D18G TTR is monomeric and highly prone to misfold and aggregate even at physiological conditions. Extremely low levels of mutant protein circulate both in human serum and cerebrospinal fluid, indicating impaired secretion of D18G TTR. Recent data show efficient selective ER-associated degradation (ERAD) of D18G TTR. One essential component of the ER-assisted folding machinery is the molecular chaperone BiP. Co-expression of BiP and D18G TTR, or BiP and wild-type (wt) TTR, or mutants A25T TTR and L55P TTR in Escherichia coli showed that only D18G TTR was significantly captured by BiP. Negligible capture of wt TTR and L55P TTR was seen and a sixfold smaller amount of A25T TTR bound to BiP compared to D18G TTR. These data correlate very well with thermodynamic and kinetic stability of the TTR variants, indicating that folding efficiency is inversely correlated to BiP capture. The complexes between BiP and D18G TTR were stable and could be isolated through affinity chromatography. Analytical ultracentrifugation and size-exclusion chromatography revealed that D18G TTR and BiP formed a mixture of 1:1 complexes and large soluble oligomers. The stoichiometry of captured D18G TTR versus BiP increased with increasing size of the oligomers. This indicates that BiP either worked as a molecular shepherd collecting the aggregation-prone mutant into stable oligomers or that BiP could bind to oligomers formed from misfolded mutant protein. Sequence analysis of bound TTR peptides to BiP revealed a bound sequence corresponding to residues 88–103 of TTR, comprising β-strand F in the folded TTR monomer constituting part of the hydrogen bonding tetramer interface in native TTR. The F-strand has also been suggested as a possible elongation region of amyloid fibrils, implicating how substoichiomeric amounts of BiP could sequester prefibrillar amyloidogenic oligomers through binding to this part of TTR. BiP binding to D18G TTR was abolished by addition of ATP. The released D18G TTR completely misfolded into amyloid aggregates as shown by ThT fluorescence and Congo red binding.

  • 119.
    Sörgjerd, Karin
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lindgren, Mikael
    Norwegian University of Science & Technology.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Hammarström , Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Prefibrillar transthyretin oligomers and cold stored native tetrameric transthyretin are cytotoxic in cell culture2008In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 377, no 4, p. 1072-1078Article in journal (Refereed)
    Abstract [en]

    Recent studies Suggest that Soluble, oligomeric species, which are intermediates in the fibril formation process in amyloid disease, might be the key species in amyloid pathogenesis. Soluble oligomers of human wild type transthyretin (TTR) were produced to elucidate oligomer properties. Employing ThT fluorescence, time-resolved fluorescence anisotropy of pyrene-labeled TTR, chemical cross-linking, and electron microscopy we demonstrated that early formed soluble oligomers (within minutes) from A-state TTR comprised on the average 20-30 TTR monomers. When administered to neuroblastoma cells these early oligomers proved highly cytotoxic and induced apoptosis after 48 h of incubation. More Mature fibrils (> 24 h of fibrillation) were non-toxic. Surprisingly, we also found that native tetrameric TTR, when purified and stored under cold conditions (4 degrees C) was highly cytotoxic. The effect Could be partially restored by increasing the temperature of the protein. The cytotoxic effects of native tetrameric TTR likely stems from a hitherto unexplored low temperature induced rearrangement of the tetramer conformation that possibly is related to the conformation of misfolded TTR in amyloigogenic oligomers.

  • 120.
    Sörgjerd, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lindgren, Mikael
    Department of Physics, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Prefibrillar Amyloid Aggregates and Cold Shocked Tetrameric Wild Type Transthyretin are CytotoxicManuscript (Other academic)
    Abstract [en]

    Recent studies suggest that soluble, oligomeric species, which are intermediates in the fibril formation process in amyloid disease, might be the key species in amyloid pathogenesis. Soluble oligomers of TTR were produced by kinetic sampling from a TTR fibrillation reaction (A-state TTR, pH 2, 100 mM NaCl). The reaction was terminated at different time points, and different states in the aggregation process were captured and analyzed to elucidate the oligomer properties followed by sampling for cytotoxicity using exposure towards human SH-SYY5 neuroblastoma cells. Employing ThT fluorescence, time-resolved fluorescence anisotropy of pyrenelabeled TTR, chemical cross-linking and electron microscopy we demonstrated that early formed oligomers from A-state TTR were soluble and comprised on the average 20-30 TTR monomers. Early oligomers were highly cytotoxic and induced apoptosis as indicated by the MTT assay and caspase-3 activation, whereas mature fibrils were non-toxic. We also indicate an activated unfolded protein response in cells exposed to oligomers as evidenced by an increased expression of the endoplasmic reticulum located molecular chaperone BiP. Following exposure, BiP appeared relocalized to the cytoplasm. Surprisingly, we also found that native tetrameric TTR purified and stored under cold conditions (4 °C) was highly cytotoxic. The effect could be partially restored by increasing the temperature of the protein. The molecular basis for this pathogenicity is rather unclear but likely stems from previously reported increased sensitivity towards dissociation and denaturation of TTR at low temperatures and opens the possibility that rearranged tetrameric TTR is cytotoxic towards neuroblastoma cells.

  • 121.
    Sörgjerd, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Wiseman, R. Luke
    Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, NY, USA.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Berg, Ina
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Budka, Herbert
    Institute of Neurology, Medical University of Vienna, Vienna, Austria.
    Nilsson, K. Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Ron, David
    Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, NY, USA.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    BiP can function as a molecular shepherd that alleviates oligomer toxicity and amass amyloidManuscript (Other academic)
    Abstract [en]

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

  • 122. Tiihonen, Mikael
    et al.
    Laurell, Fredrik
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Lindgren, Mikael
    A UV laser source for biological and chemical sensing2004In: Laser Radar technology for remote Sensing,2004, Christian Werner , 2004, p. 127-Conference paper (Refereed)
    Abstract [en]

      

  • 123.
    Usmani, Shariq M.
    et al.
    Ulm University Medical Center, Germany .
    Zirafi, Onofrio
    Ulm University Medical Center, Germany .
    Mueller, Janis A.
    Ulm University Medical Center, Germany .
    Sandi-Monroy, Nathallie L.
    Ulm University Medical Center; Kinderwunsch-Zentrum Ulm, Germany.
    Yadav, Jay K.
    Ulm University, Germany.
    Meier, Christoph
    Ulm University, Germany .
    Weil, Tanja
    Ulm University, Germany.
    Roan, Nadia R.
    University of California at San Francisco, USA .
    Greene, Warner C.
    University of California at San Francisco, USA.
    Walther, Paul
    Ulm University, Germany.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Wetzel, Ronald
    University of Pittsburgh, PA, USA .
    Pilcher, Christopher D.
    University of California, San Francisco, USA .
    Gagsteiger, Friedrich
    Kinderwunsch-Zentrum Ulm, Germany.
    Fändrich, Marcus
    Ulm University, Germany.
    Kirchhoff, Frank
    Ulm University Medical Center, Germany.
    Münch, Jan
    Ulm University Medical Center, Germany.
    Direct visualization of HIV-enhancing endogenous amyloid fibrils in human semen2014In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, p. 3508-Article in journal (Refereed)
    Abstract [en]

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

  • 124.
    Villebeck, Laila
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Klang, Hanna
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Moparthi, Satish Babu
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lindgren, Mikael
    Department of Physics, The Norwegian University of Science and Technology, 7491 Trondheim, Norway.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Mapping the Different Interactions between Eukaryotic β-actin and the Group I (GroEL) and Group II (TRiC) ChaperoninsManuscript (preprint) (Other academic)
    Abstract [en]

    Productive folding to the native state of the abundant eukaryotic protein actin is dependent on the chaperonin TRiC. The prokaryotic chaperonin GroEL also recognizes actin, but this interaction does not lead to the correct folding of actin. It is well established that GroEL interacts with non-native proteins through hydrophobic interactions. The characteristics of the interactions between TRiC and its target proteins are however unclear. In this study, we present multiple site-directed cysteine labeling and fluorescence measurements indicating that actin initially binds to TRiC through several interaction sites and that the surfaces of the interaction areas on the walls of the TRiC chamber present both polar and hydrophobic residues. At a later stage in the chaperonin cycle, the binding of ATP causes conformational changes in the chaperonin, which leads to a presentation of a more hydrophobic milieu in TRiC chamber. The conformational changes of the chaperonin causes rearrangements of the actin molecule and new interactions are proposed to be formed. Additionally, we show that the initial binding of actin to TRiC leads to a re-modeling of the nucleotide-binding cleft in actin. We also present data indicating that GroEL presents less specific interaction areas towards the bound actin than TRiC does. The interactions between actin and GroEL are tight and of hydrophobic character. No re-modeling of the nucleotide-binding cleft was obtained in the actin-GroEL complex. We conclude that the interactions between actin and TRiC are of both polar and hydrophobic character, the nature of the interactions are different in the prokaryotic and eukaryotic chaperonins, and the rearrangements of the nucleotide binding cleft of actin seen in the chaperonin cycle of TRiC do not occur in GroEL. We suggest that the rearrangements of the nucleotide-binding site in actin are critical for productive folding of actin.

  • 125.
    Villebeck, Laila
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Moparthi, Satish Babu
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Interactions Between the Bacterial β-actin Homologue MreB and the Group I Chaperonin GroEL and Group II Chaperonin TRiCManuscript (preprint) (Other academic)
    Abstract [en]

    This pilot study on the interaction between MreB andthe chaperonins TRiC and GroEL indicates that thefolding of the actin ancestor was facilitated by thechaperonins. From an evolutionary point of view, it isinteresting to investigate the nature of the bindinginteraction between the prokaryotic system MreB-GroELand compare it to the binding interaction between actinand TRiC and the following questions will be addressed:Does MreB refold in a spontaneous manner or is itsfolding dependent on the action of a chaperonin (GroEL)as in the case of actin folding (TRiC)? Does MreB bind ina similar stretched manner to GroEL as actin binds toTRiC (4, 11), or is the “general” binding inducedunfolding sufficient for guiding MreB to the native state?How does the MreB molecule interact with TRiC, is therea similar stretching as for actin? Are there any analoguessequences between actin and TRiC that are recognized byTRiC and/or GroEL?

    Two single variants where cysteines have beenintroduced at positions 69 and 245 in E. coli MreB(Figure 1 B). These positions are situated at the tips of thecorresponding subdomains 2 and 4 of the actin molecule(4, 12). The double variant N69C/V245C has also beenconstructed. The three variants will be produced andlabeled with fluorescein and subsequent homo-FRETmeasurements will be performed on MreB bound toGroEL, TRiC and GroES. The results will be comparedto the results on actin bound to the chaperonins toinvestigate how the chaperonin-dependent folding ofactin homologues has evolved.

  • 126.
    Villebeck, Laila
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Moparthi, Satish Babu
    Lindgren, Mikael
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Different Conformational Effects when β-actin Binds to the Bacterial Chaperonin GroEL and the Eukaryotic Chaperonin TRiC2007Article in journal (Refereed)
  • 127.
    Villebeck, Laila
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Moparthi, Satish Babu
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lindgren, Mikael
    Department of Physics, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Domain-specific chaperone-induced expansion is required for ß-actin folding: a comparison of ß-actin conformations upon interactions with GroEL and tail-less complex polypeptide 1 ring complex (TRiC)2007In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, no 44, p. 12639-12647Article in journal (Refereed)
    Abstract [en]

    Actin, an abundant cytosolic protein in eukaryotic cells, is dependent on the interaction with the chaperonin tail-less complex polypeptide 1 ring complex (TRiC) to fold to the native state. The prokaryotic chaperonin GroEL also binds non-native ß-actin, but is unable to guide ß-actin toward the native state. In this study we identify conformational rearrangements in ß-actin, by observing similarities and differences in the action of the two chaperonins. A cooperative collapse of ß-actin from the denatured state to an aggregation-prone intermediate is observed, and insoluble aggregates are formed in the absence of chaperonin. In the presence of GroEL, however, >90% of the aggregation-prone actin intermediate is kept in solution, which shows that the binding of non-native actin to GroEL is effective. The action of GroEL on bound flourescein-labeled ß-actin was characterized, and the structural rearrangement was compared to the case of the ß-actin-TRiC complex, employing the homo fluorescence resonance energy transfer methodology previously used [Villebeck, L., Persson, M., Luan, S.-L., Hammarström, P., Lindgren, M., and Jonsson, B.-H. (2007) Biochemistry 46 (17), 5083-93]. The results suggest that the actin structure is rearranged by a "binding-induced expansion" mechanism in both TRiC and GroEL, but that binding to TRiC, in addition, causes a large and specific separation of two subdomains in the ß-actin molecule, leading to a distinct expansion of its ATP-binding cleft. Moreover, the binding of ATP and GroES has less effect on the GroEL-bound ß-actin molecule than the ATP binding to TRiC, where it leads to a major compaction of the ß-actin molecule. It can be concluded that the specific and directed rearrangement of the ß-actin structure, seen in the natural ß-actin-TRiC system, is vital for guiding ß-actin to the native state. © 2007 American Chemical Society.

  • 128.
    Villebeck, Laila
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Persson, Malin
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Luan, Shi-Lu
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Lindgren, Mikael
    Department of Physics, The Norwegian University of Science and Technology, Trondheim, Norway.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Conformational Rearrangements of Tail-less Complex Polypeptide 1 (TCP-1) Ring Complex (TRiC)-Bound Actin2007In: Biochemistry, ISSN 0006-2960, Vol. 46, no 17, p. 5083-5093Article in journal (Refereed)
    Abstract [en]

    The mechanism of chaperonins is still under intense investigation. Earlier studies by others and us on the bacterial chaperonin GroEL points to an active role of chaperonins in unfolding the target protein during initial binding. Here, a natural eukaryotic chaperonin system [tail-less complex polypeptide 1 (TCP-1) ring complex (TRiC) and its target protein actin] was investigated to determine if the active participation of the chaperonin in the folding process is evolutionary-conserved. Using fluorescence resonance energy transfer (FRET) measurements on four distinct doubly fluorescein-labeled variants of actin, we have obtained a fairly detailed map of the structural rearrangements that occur during the TRiC−actin interaction. The results clearly show that TRiC has an active role in rearranging the bound actin molecule. The target is stretched as a consequence of binding to TRiC and further rearranged in a second step as a consequence of ATP binding; i.e., the mechanism of chaperonins is conserved during evolution.

  • 129.
    Wegenast-Braun, Bettina M.
    et al.
    Hertie Institute Clin Brain Research, Germany German Centre Neurodegenerat Disease, Germany .
    Skodras, Angelos
    Hertie Institute Clin Brain Research, Germany German Centre Neurodegenerat Disease, Germany .
    Bayraktar, Gonca
    Hertie Institute Clin Brain Research, Germany University of Tubingen, Germany German Centre Neurodegenerat Disease, Germany .
    Mahler, Jasmin
    Hertie Institute Clin Brain Research, Germany University of Tubingen, Germany German Centre Neurodegenerat Disease, Germany .
    Fritschi, Sarah K.
    Hertie Institute Clin Brain Research, Germany University of Tubingen, Germany German Centre Neurodegenerat Disease, Germany .
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Mason, Jeffrey
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering.
    Liebig, Christian
    Hertie Institute Clin Brain Research, Germany German Centre Neurodegenerat Disease, Germany .
    Jucker, Mathias
    Hertie Institute Clin Brain Research, Germany German Centre Neurodegenerat Disease, Germany .
    Spectral Discrimination of Cerebral Amyloid Lesions after Peripheral Application of Luminescent Conjugated Oligothiophenes2012In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 181, no 6, p. 1953-1960Article in journal (Refereed)
    Abstract [en]

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

  • 130. Wirehn, J.
    et al.
    Carlsson, Karin
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Herland, Anna
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics .
    Persson, E.
    Haemostasis Biochemistry, Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark.
    Carlsson, Uno
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Svensson, Magdalena
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Activity, folding, misfolding, and aggregation in vitro of the naturally occurring human tissue factor mutant R200W2005In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 44, no 18, p. 6755-6763Article in journal (Refereed)
    Abstract [en]

    Tissue factor (TF), a small transmembrane receptor, binds factor VIIa (FVIIa), and the formed complex initiates blood coagulation by proteolytic activation of substrate factors IX and X. A naturally occurring mutation in the human TF gene was recently reported, where a single-base substitution results in an R200W mutation in the TF extracellular domain [Zawadzki, C., Preudhomme, C., Gavériaux, V., Amouyel, P., and Jude, B. (2002) Thromb. Haemost. 87, 540-541]. This mutation appears to be associated with low monocyte TF expression and may protect against thrombosis but has not been associated with any pathological condition, and individuals who present the heterozygous trait appear healthy. Here, we report the activity, folding, and aggregation behavior of the R200W mutant of the 219-residue soluble extracellular domain of TF (sTFR200W) compared to that of the wild-type protein (sTF wt). No differences in stability or FVIIa cofactor activity but an impaired ability to promote FX activation at physiological conditions between the sTFR200W mutant and sTFwt were evident. Increased binding of 1-anilino-8-naphthalene-sulfonic acid (ANS) to sTFR200W indicated a population of partially folded intermediates during denaturation. sTFR200W showed a dramatically increased propensity for aggregate formation compared to sTFwt at mildly acidic pHs, with an increased rate of aggregation during conditions, promoting the intermediate state. The lowered pH resistance could explain the loss of sTFR200W in vivo because of aggregation of the mutant. The intrinsic structure of the sTF aggregates appears reminiscent of amyloid fibrils, as revealed by thioflavin T fluorescence, atomic force microscopy, and transmission electron microscopy. We conclude that the lowered activity for FX activation and the propensity of the mutant protein to misfold and aggregate will both contribute to decreased coagulation activity in TFR200W carriers, which could protect from thrombotic disease. © 2005 American Chemical Society.

  • 131.
    Zako, T.
    et al.
    Bioengineering Laboratory, RIKEN Institute, Saitama, Japan.
    Kobayashi, T.
    Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
    Sakono, M.
    Bioengineering Laboratory, RIKEN Institute, Saitama, Japan.
    Lindgren, M.
    Department of Physics, The Norwegian University of Science and Technology, Trondheim, Norway.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Maeda, M.
    Bioengineering Laboratory, RIKEN Institute, Saitama, Japan.
    Structure and cytotoxicity of novel insulin noodle-like filamentous amyloids2009In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, no Suppl. s1, p. 173-173Article in journal (Other academic)
    Abstract [en]

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

    References:

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

    2. Chem Bio Chem 2006; 7:1096.

    3. ACS Chem Biol 2007; 4: 553.

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

  • 132.
    Zako, Tamotsu
    et al.
    Bioengineering Laboratory, RIKEN Institute, Wako, Saitama, Japan.
    Sakono, Masafumi
    Bioengineering Laboratory, RIKEN Institute, Wako, Saitama, Japan.
    Kobayashi, Takahiro
    Sörgjerd, Karin
    Bioengineering Laboratory, RIKEN Institute, Wako, Saitama, Japan.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, The Institute of Technology.
    Lindgren, Mikael
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Maeda, Mizuo
    Bioengineering Laboratory, RIKEN Institute, Wako, Saitama, Japan.
    Cell Interaction Study of Amyloid by Using Luminescent Conjugated Polythiophene: Implication that Amyloid Cytotoxicity Is Correlated withProlonged Cellular Binding2012In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 13, no 3, p. 358-363Article in journal (Refereed)
    Abstract [en]

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

  • 133.
    Zetterberg, Henrik
    et al.
    University of Gothenburg, Sweden UCL Institute Neurol, England .
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Editorial Material: Power tools for Alzheimers disease - an electrochemical preamp for A beta2012In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 122, no 2, p. 231-232Article in journal (Other academic)
    Abstract [en]

    n/a

  • 134.
    Zhang, Jun
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Konsmo, Audun
    Norwegian Univ Sci and Technol, Norway.
    Sandberg, Alexander
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Obermuller, Ulrike
    Univ Tubingen, Germany; DZNE German Ctr Neurodegenerat Dis, Germany.
    Wegenast-Braun, Bettina M.
    Univ Tubingen, Germany; DZNE German Ctr Neurodegenerat Dis, Germany.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lindgren, Mikael
    Norwegian Univ Sci and Technol, Norway.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Phenolic Bis-styrylbenzo[c]-1,2,5-thiadiazoles as Probes for Fluorescence Microscopy Mapping of A beta Plaque Heterogeneity2019In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 62, no 4, p. 2038-2048Article in journal (Refereed)
    Abstract [en]

    A fluorescent bis-styryl-benzothiadiazole (BTD) with carboxylic acid functional groups (X-34/Congo red analogue) showed lower binding affinity toward A beta 1-42 and A beta 1-40 fibrils than its neutral analogue. Hence, variable patterns of neutral OH-substituted bis-styryl-BTDs were generated. All bis-styryl-BTDs showed higher binding affinity to A beta 1-42 fibrils than to A beta 1-40 fibrils. The para-OH on the phenyl rings was beneficial for binding affinity while a meta-OH decreased the affinity. Differential staining of transgenic mouse A beta amyloid plaque cores compared to peripheral coronas using neutral compared to anionic bis-styryl ligands indicate differential recognition of amyloid polymorphs. Hyperspectral imaging of transgenic mouse A beta plaque stained with uncharged para-hydroxyl substituted bis-styryl-BTD implicated differences in binding site polarity of polymorphic amyloid plaque. Most properties of the corresponding bis-styryl-BTD were retained with a rigid alkyne linker rendering a probe insensitive to cis trans isomerization. These new BTDbased ligands are promising probes for spectral imaging of different A beta fibril polymorphs.

  • 135.
    Zhang, Jun
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Sandberg, Alexander
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Konsmo, Audun
    Norwegian Univ Sci and Technol, Norway.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    LeVine, Harry III
    Univ Kentucky, KY 40536 USA.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Norwegian Univ Sci and Technol, Norway.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Detection and Imaging of A beta 1-42 and Tau Fibrils by Redesigned Fluorescent X-34 Analogues2018In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, no 28, p. 7210-7216Article in journal (Refereed)
    Abstract [en]

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

  • 136.
    Zhang, Jun
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Chemistry.
    Sandberg, Alexander
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lindgren, Mikael
    Department of Physics, The Norwegian University of Science and Technology, Trondheim, Norway.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    trans-Stilbenoids with Extended Fluorescence Lifetimes for the Characterization of Amyloid Fibrils2017In: ACS Omega, ISSN 2470-1343, Vol. 2, no 8, p. 4693-4704Article in journal (Refereed)
    Abstract [en]

    It was previously reported that two naphthyl-based trans-stilbene probes, (E)-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol (1) and (E)-4-(2-(naphthalen-2-yl)vinyl)benzene-1,2-diol (3), can bind to both native transthyretin (TTR) and misfolded protofibrillar TTR at physiological concentrations, displaying distinct emission maxima bound to the different conformational states (>100 nm difference). To further explore this amyloid probe scaffold to obtain extended fluorescence lifetimes, two new analogues with expanded aromatic ring systems (anthracene and pyrene), (E)-4-(2-(anthracen-2-yl)vinyl)benzene-1,2-diol (4) and (E)-4-(2-(pyren-2-yl)vinyl)benzene-1,2-diol (5), were synthesized employing the palladium-catalyzed Mizoroki–Heck reaction. (E)-4-Styrylbenzene-1,2-diol (2), 3, 4, and 5 were investigated with respect to their photophysical properties in methanol and when bound to insulin, lysozyme, and Aβ1-42 fibrils, including time-resolved fluorescence measurements. In conclusion, 4 and 5 can bind to both native and fibrillar TTR, becoming highly fluorescent. Compounds 2–5 bind specifically to insulin, lysozyme, and Aβ1-42 fibrils with an apparent fluorescence intensity increase and moderate binding affinities. The average fluorescence lifetimes of the probes bound to Aβ1-42 fibrils are 1.3 ns (2), 1.5 ns (3), 5.7 ns (4), and 29.8 ns (5). In summary, the variable aromatic moieties of the para-positioned trans-stilbenoid vinyl-benzene-1,2-diol with benzene, naphthalene, anthracene, and pyrene showed that the extended conjugated systems retained the amyloid targeting properties of the probes. Furthermore, both the anthracene and pyrene moieties extensively enhanced the fluorescence intensity and prolonged lifetimes. These attractive probe properties should improve amyloid detection and characterization by fluorescence-based techniques.

  • 137.
    Zhang, Jun
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Wang, Jun
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Sandberg, Alexander
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    LeVine, Harry III
    Sanders-Brown Center on Aging, University of Kentucky, KY 40536-0230, Lexington, USA..
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Durbeej, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Department of Physics, Norwegian University of Science and Technology, 7491, Trondheim, Norway..
    Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.2018In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 19, no 22, p. 3001-3009Article in journal (Refereed)
    Abstract [en]

    Two analogues to the fluorescent amyloid probe 2,5-bis(4'-hydroxy-3'-carboxy-styryl)benzene (X-34) were synthesized based on the trans-stilbene pyrene scaffold (Py1SA and Py2SA). The compounds show strikingly different emission spectra when bound to preformed Aβ1-42 fibrils. This remarkable emission difference is retained when bound to amyloid fibrils of four distinct proteins, suggesting a common binding configuration for each molecule. Density functional theory calculations show that Py1SA is twisted, while Py2SA is more planar. Still, an analysis of the highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LUMOs) of the two compounds indicates that the degree of electronic coupling between the pyrene and salicylic acid (SA) moieties is larger in Py1SA than in Py2SA. Excited state intramolecular proton transfer (ESIPT) coupled-charge transfer (ICT) was observed for the anionic form in polar solvents. We conclude that ICT properties of trans-stilbene derivatives can be utilized for amyloid probe design with large changes in emission spectra and decay times from analogous chemical structures depending on the detailed physical nature of the binding site.less thanbr /greater than (© 2018 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim.)

  • 138.
    Åslund, Andreas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Herland, Anna
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Studies of luminescent conjugated polythiophene derivatives-Enhanced spectral discrimination of protein conformational states2007In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 18, no 6, p. 1860-1868Article in journal (Refereed)
    Abstract [en]

    Improved probes for amyloid fibril formation are advantageous for the early detection and better understanding of this disease-associated process. Here, we report a comparative study of eight luminescent conjugated polythiophene derivates (LCPs) and their discrimination of a protein (insulin) in the native or amyloid-like fibrillar state. For two of the LCPs, the synthesis is reported. Compared to their monomer-based analogues, trimer-based LCPs showed significantly better optical signal specificity for amyloid-like fibrils, seen from increased quantum yield and spectral shift. The trimer-based LCPs alone were highly quenched and showed little interaction with native insulin, as seen from analytical ultracentrifugation and insignificant spectral differences from the trimer-based LCP in buffered and native protein solution. Hence, the trimer-based LCPs showed enhanced discrimination between the amyloid-like fibrillar state and the corresponding native protein.

  • 139.
    Åslund, Andreas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Sigurdson, Christina J
    Institute of Neuropathology, Department of Pathology, Universitätsspital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Grathwohl, Stefan
    Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, D-72076 Tuebingen, Germany.
    Bolmont, Tristan
    Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, D-72076 Tuebingen, Germany.
    Dickstein, Dara L
    Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
    Glimsdal, Eirik
    Department of Physics, Norwegian University of Science and Technology, N-7491 Trondheim, Norway.
    Prokop, Stefan
    Department of Neuropathology, Charité-Universitätsmedizin Berlin, D-13353 Berlin, Germany.
    Lindgren, Mikael
    Department of Physics, Norwegian University of Science and Technology, N-7491 Trondheim, Norway.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Holtzman, David M
    Department of Neurology, Alzheimer’s Disease Research Center, Washington University, St. Louis, Missouri 63110, USA.
    Hof, Patrick R
    Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
    Heppner, Frank L
    Department of Neuropathology, Charité-Universitätsmedizin Berlin, D-13353 Berlin, Germany.
    Gandy, Samuel
    Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
    Jucker, Mathias
    Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, D-72076 Tuebingen, Germany.
    Aguzzi, Adriano
    Institute of Neuropathology, Department of Pathology, Universitätsspital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Novel Pentameric Thiophene Derivatives for in Vitro and in Vivo Optical Imaging of a Plethora of Protein Aggregates in Cerebral Amyloidoses2009In: ACS CHEMICAL BIOLOGY, ISSN 1554-8929, Vol. 4, no 8, p. 673-684Article in journal (Refereed)
    Abstract [en]

    Molecular probes for selective Identification of protein aggregates are important to advance our understanding of the molecular pathogenesis underlying cerebral amyloidoses. Here we report the chemical design of pentameric thiophene derivatives, denoted luminescent conjugated oligothiophenes (LCOs), which could be used for real-time visualization of cerebral protein aggregates in transgenic mouse models of neurodegenerative diseases by multiphoton microscopy. One of the LCOs, p-FTAA, could be utilized for ex vivo spectral assignment of distinct prion deposits from two, mouse-adapted prion strains. p-FTAA also revealed a transient soluble pre-fibrillar non-thioflavinophilic A beta-assemblies during in vitro fibrillation of A beta peptides. In brain tissue samples, A beta deposits and neurofibrillary tangles (NFTs) were readily identified by a strong fluorescence from p-FTAA and the LCO staining showed complete co-localliation with conventional antibodies (6E10 and AT8). In addition, a patchy islet-like staining of individual A beta plaque was unveiled by the anti-oligomer A11 antibody during co-staining with p-FTAA. The major hallmarks of Alzheimers disease, namely, A beta aggregates versus NFTs, could also be distinguished because of distinct emission spectra from p-FTAA. Overall, we demonstrate that LCOs can be utilized as powerful practical research tools for studying protein aggregation diseases and facilitate the study of amyloid origin, evolution and maturation, A beta-tau interactions, and pathogenesis both ex vivo and in vivo.

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