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Zhang, J., Wang, J., Sandberg, A., Wu, X., Nyström, S., LeVine, H. I., . . . Lindgren, M. (2018). Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.. ChemPhysChem, 19(22), 3001-3009
Open this publication in new window or tab >>Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.
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2018 (English)In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 19, no 22, p. 3001-3009Article in journal (Refereed) Published
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.)

Place, publisher, year, edition, pages
Weinheim, Germany: Wiley-VCH Verlag, 2018
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:liu:diva-152767 (URN)10.1002/cphc.201800823 (DOI)000450672100006 ()30183138 (PubMedID)
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-11-08
Sandberg, A. & Nyström, S. (2018). Purification and Fibrillation of Recombinant Human Amyloid-ß, Prion Protein, and Tau Under Native Conditions. In: Einar M. Sigurdsson, Miguel Calero and María Gasset (Ed.), Amyloid Proteins: Methods and Protocols (pp. 147-166). Humana Press, 1779
Open this publication in new window or tab >>Purification and Fibrillation of Recombinant Human Amyloid-ß, Prion Protein, and Tau Under Native Conditions
2018 (English)In: Amyloid Proteins: Methods and Protocols / [ed] Einar M. Sigurdsson, Miguel Calero and María Gasset, Humana Press, 2018, Vol. 1779, p. 147-166Chapter in book (Refereed)
Abstract [en]

Protein misfolding, aggregation, and amyloid formation is involved in a large number of diseases. Recombinantly expressed proteins to study the amyloid fibril formation process are important for mechanistic studies. We here report protocols for production, purification, and fibrillation of three different proteins commonly found in cerebral amyloid; Aß and Tau found in Alzheimers disease, Chronic traumatic brain injury, Corticobasal degeneration, and Progressive Supranuclear Palsy and human prion protein found in Creutzfeldt-Jakobs disease. The three protocols have in common that the protein is in a pH-neutral phosphate saline buffer during fibrillation to mimic their endogenous near physiological environment.

Place, publisher, year, edition, pages
Humana Press, 2018
Series
Methods in Molecular Biology, E-ISSN 1940-6029 ; 1779
Keywords
Amyloid; Aß; Fibrillation; Neurodegenerative disease; Prion protein; Purification; Recombinant; Tau
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:liu:diva-152517 (URN)10.1007/978-1-4939-7816-8_10 (DOI)29886532 (PubMedID)9781493978151 (ISBN)9781493978168 (ISBN)
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-11-08
Nyström, S., Vahdat Shariat Panahi, A., Nilsson, P., Westermark, P., Westermark, G. T., Hammarström, P. & Lundmark, K. (2017). Seed-dependent templating of murine AA amyloidosis. Amyloid: Journal of Protein Folding Disorders, 24(sup1), 140-141
Open this publication in new window or tab >>Seed-dependent templating of murine AA amyloidosis
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2017 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, no sup1, p. 140-141Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
Taylor & Francis, 2017
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-145569 (URN)10.1080/13506129.2017.1290599 (DOI)000399943700076 ()28434369 (PubMedID)2-s2.0-85018736877 (Scopus ID)
Available from: 2018-03-25 Created: 2018-03-25 Last updated: 2019-11-08Bibliographically approved
Zhang, J., Sandberg, A., Wu, X., Nyström, S., Lindgren, M., Konradsson, P. & Hammarström, P. (2017). trans-Stilbenoids with Extended Fluorescence Lifetimes for the Characterization of Amyloid Fibrils. ACS Omega, 2(8), 4693-4704
Open this publication in new window or tab >>trans-Stilbenoids with Extended Fluorescence Lifetimes for the Characterization of Amyloid Fibrils
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2017 (English)In: ACS Omega, ISSN 2470-1343, Vol. 2, no 8, p. 4693-4704Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
Keywords
Fluorescence; Glycoproteins; Molecular association; Molecular recognition; Optical materials; Quantum transition; Spectra
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-151658 (URN)10.1021/acsomega.7b00535 (DOI)000409924000069 ()
Available from: 2018-09-28 Created: 2018-09-28 Last updated: 2019-11-08Bibliographically approved
Klingstedt, T., Shirani, H., Mahler, J., Wegenast-Braun, B. M., Nyström, S., Goedert, M., . . . Nilsson, P. (2015). Distinct Spacing Between Anionic Groups: An Essential Chemical Determinant for Achieving Thiophene-Based Ligands to Distinguish Beta-Amyloid or Tau Polymorphic Aggregates. Chemistry - A European Journal, 21(25), 9072-9082
Open this publication in new window or tab >>Distinct Spacing Between Anionic Groups: An Essential Chemical Determinant for Achieving Thiophene-Based Ligands to Distinguish Beta-Amyloid or Tau Polymorphic Aggregates
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2015 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 25, p. 9072-9082Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Wiley-VCH Verlag, 2015
Keywords
aggregates; Alzheimers disease; fluorescence; luminescent conjugated oligothiophenes; proteins
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-120041 (URN)10.1002/chem.201500556 (DOI)000355762900019 ()26013403 (PubMedID)
Note

Funding Agencies|Swedish Foundation for Strategic Research; Swedish Alzheimer Foundation; European Research Council Starting Independent Researcher Grant (MUMID)

Available from: 2015-07-06 Created: 2015-07-06 Last updated: 2019-11-08
Nyström, S. & Hammarström, P. (2015). Generic amyloidogenicity of mammalian prion proteins from species susceptible and resistant to prions. Scientific Reports, 5(10101)
Open this publication in new window or tab >>Generic amyloidogenicity of mammalian prion proteins from species susceptible and resistant to prions
2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 10101Article in journal (Refereed) Published
Abstract [en]

Prion diseases are lethal, infectious diseases associated with prion protein (PrP) misfolding. A large number of mammals are susceptible to both sporadic and acquired prion diseases. Although PrP is highly conserved and ubiquitously expressed in all mammals, not all species exhibit prion disease. By employing full length recombinant PrP from five known prion susceptible species (human, cattle, cat, mouse and hamster) and two species considered to be prion resistant (pig and dog) the amyloidogenicity of these PrPs has been delineated. All the mammalian PrPs, even from resistant species, were swiftly converted from the native state to amyloid-like structure when subjected to a native condition conversion assay. The PrPs displayed amyloidotypic tinctorial and ultrastructural hallmarks. Self-seeded conversion of the PrPs displayed significantly decreased lag phases demonstrating that nucleation dependent polymerization is a dominating mechanism in the fibrillation process. Fibrils from A beta 1-40, A beta 1-42, Lysozyme, Insulin and Transthyretin did not accelerate conversion of HuPrP whereas fibrils from HuPrP90-231 and HuPrP121-231 as well as full length PrPs of all PrPs efficiently seeded conversion showing specificity of the assay requiring the C-terminal PrP sequence. Our findings have implications for PrP misfolding and could have ramifications in the context of prion resistant species and silent carriers.

Place, publisher, year, edition, pages
Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group, 2015
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-118855 (URN)10.1038/srep10101 (DOI)000354273600003 ()25960067 (PubMedID)
Note

Funding Agencies|Swedish research council [2011-5804]

Available from: 2015-06-08 Created: 2015-06-04 Last updated: 2019-11-08
Hammarström, P. & Nyström, S. (2015). Porcine prion protein amyloid. Prion, 9(4), 266-277
Open this publication in new window or tab >>Porcine prion protein amyloid
2015 (English)In: Prion, ISSN 1933-6896, E-ISSN 1933-690X, Vol. 9, no 4, p. 266-277Article in journal (Refereed) Published
Abstract [en]

Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of mammalian species including humans. Mammals and by-products thereof which are frequently encountered in daily life are most important for human health. It is established that bovine prions (BSE) can infect humans while there is no such evidence for any other prion susceptible species in the human food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or susceptible and resistant pets (cat and dogs, respectively). PrPs from these species have been characterized using biochemistry, biophysics and neurobiology. Recently we studied PrPs from several mammals in vitro and found evidence for generic amyloidogenicity as well as cross-seeding fibril formation activity of all PrPs on the human PrP sequence regardless if the original species was resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was among the studied. Experimentally inoculated pigs as well as transgenic mouse lines overexpressing porcine PrP have, in the past, been used to investigate the possibility of prion transmission in pigs. The pig is a species with extraordinarily wide use within human daily life with over a billion pigs harvested for human consumption each year. Here we discuss the possibility that the largely prion disease resistant pig can be a clinically silent carrier of replicating prions.

Place, publisher, year, edition, pages
Taylor andamp; Francis: STM, Behavioural Science and Public Health Titles, 2015
Keywords
prion; pig; amyloid fibril; misfolding; transmissibility; seeding; TSE; prion strain; strain adaptation
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-121140 (URN)10.1080/19336896.2015.1065373 (DOI)000359713000004 ()26218890 (PubMedID)
Note

Funding Agencies|Gooran Gustafsson foundation; Swedish research council Grant [2011-5804]; Swedish Alzheimer association

Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2019-11-08
Herrmann, U. S., Schuetz, A. K., Shirani, H., Huang, D., Saban, D., Nuvolone, M., . . . Aguzzi, A. (2015). Structure-based drug design identifies polythiophenes as antiprion compounds. Science Translational Medicine, 7(299), 299ra123
Open this publication in new window or tab >>Structure-based drug design identifies polythiophenes as antiprion compounds
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2015 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, no 299, p. 299ra123-Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2015
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-121758 (URN)10.1126/scitranslmed.aab1923 (DOI)000360940300004 ()26246168 (PubMedID)
Note

Funding Agencies|European Research Council; European Union; Swiss National Foundation; Novartis Research Foundation; University of Zurich; Center for Clinical Research, University Hospital Zurich; Collegio Ghislieri, Pavia; Foundation for Research at the Medical Faculty of the University of Zurich; Swedish Foundation for Strategic Research; Swiss National Science Foundation [200020_146757, 315230_149897]; European Union Seventh Framework Program [Bio-NMR 261863]; Agence Nationale de la Recherche [ANR-11-BSV-8021-01, ANR-12-BS08-0013-01]; FP-7 EU-Health project LUPAS

Available from: 2015-10-06 Created: 2015-10-05 Last updated: 2019-11-08
Nyström, S. & Hammarström, P. (2014). Is the prevalent human prion protein 129M/V mutation a living fossil from a Paleolithic panzootic superprion pandemic?. Prion, 8(1)
Open this publication in new window or tab >>Is the prevalent human prion protein 129M/V mutation a living fossil from a Paleolithic panzootic superprion pandemic?
2014 (English)In: Prion, ISSN 1933-6896, E-ISSN 1933-690X, Vol. 8, no 1Article in journal (Refereed) Published
Abstract [en]

Prion diseases are consistently associated with prion protein (PrPC) misfolding rendering a cascade of auto-catalytic self-perpetuation of misfolded PrP in an afflicted individual. The molecular process is intriguingly similar to all known amyloid diseases both local and systemic. The prion disease is also infectious by the transfer of misfolded PrP from one individual to the next. Transmissibility is surprisingly efficient in prion diseases and given the rapid disease progression following initial symptoms the prionoses stand out from other amyloidoses, which all may be transmissible under certain circumstances. The nature of the infectious prion as well as the genotype of the host is important for transmissibility. For hitherto unexplained reasons the majority of Europeans carry a missense mutation on one or both alleles of the PrP gene (PRNP), and hence express a variant of PrP with a substitution for valine (V) instead of methionine (M) in position 129. In fact the 129M/V variant is very common in all populations except for the Japanese. Sporadic Creutzfeldt-Jakob disease is a disease rarely striking people below the age of 60, where homozygosity especially 129MM is a very strong risk factor. Paradoxically, the 129M/V polymorphism suggestive of heterozygote advantage is one of the most clear cut disease associated traits of the human population, yet prion disease is extraordinarily rare. The genetic basis for how this trait spread with such prevalence within human populations is still target to investigations and deserves attention. This short essay represents a somewhat provocative hypothetical notion of a possible ancient significance of this polymorphism.

Place, publisher, year, edition, pages
Landes Bioscience, 2014
Keywords
Pleistocene; extinction; hyperdisease; prion; 129; panzootic; megafauna; polymorphism
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-106527 (URN)10.4161/pri.27601 (DOI)000334116900002 ()
Available from: 2014-05-12 Created: 2014-05-09 Last updated: 2019-11-08
Bagheri, M., Rezakhani, A., Nyström, S., Turkina, M., Roghani, M., Hammarström, P. & Mohseni, S. (2013). Amyloid Beta1-40-Induced Astrogliosis and the Effect of Genistein Treatment in Rat: A Three-Dimensional Confocal Morphometric and Proteomic Study. PLoS ONE, 8(10)
Open this publication in new window or tab >>Amyloid Beta1-40-Induced Astrogliosis and the Effect of Genistein Treatment in Rat: A Three-Dimensional Confocal Morphometric and Proteomic Study
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10Article in journal (Refereed) Published
Abstract [en]

Astrocytes are highly involved in regulation and homeostasis of the extracellular environment in the healthy brain. In pathological conditions, these cells play a major role in the inflammatory response seen in CNS tissues, which is called reactive astrogliosis and includes hypertrophy and proliferation of astrocytes. Here, we performed 3D confocal microscopy to evaluate the morphological response of reactive astrocytes positive for glial fibrillary acidic protein (GFAP) in rats, to the presence of Aβ1–40 in the rat brain before and after treatment with genistein. In 50 astrocytes per animal, we measured the volume and surface area for the nucleus, cell body, the entire cell, the tissue covered by single astrocytes and quantified the number and length of branches, the density of the astrocytes and the intensity of GFAP immunoreactivity. Injecting Aβ1–40 into the brain of rats caused astrogliosis indicated by increased values for all measured parameters. Mass spectrometric analysis of hippocampal tissue in Aβ1–40-injected brain showed decreased amounts of tubulins, enolases and myelin basic protein, and increased amounts of dihydropyrimidinase-related protein 2. In Aβ1–40-injected rats pretreated with genistein, GFAP intensity was decreased to the sham-operated group level, and Aβ1–40-induced astrogliosis was significantly ameliorated.

Place, publisher, year, edition, pages
Public Library of Science, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-101388 (URN)10.1371/journal.pone.0076526 (DOI)000325810900075 ()
Note

Funding Agencies|County Council of Ostergotland (Sweden)||Linkoping University||Cellular and Molecular Research Center||Tehran University of Medical Sciences (Tehran, Iran)||

Available from: 2013-11-22 Created: 2013-11-21 Last updated: 2019-11-08
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ORCID iD: ORCID iD iconorcid.org/0000-0002-4303-4783

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