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Hammarström, P. (2019). BIOLUMINESCENCE IMAGING Photonic amyloids. Nature Photonics, 13(7), 442-444
Open this publication in new window or tab >>BIOLUMINESCENCE IMAGING Photonic amyloids
2019 (English)In: Nature Photonics, ISSN 1749-4885, Vol. 13, no 7, p. 442-444Article in journal (Refereed) Published
Abstract [en]

Emerging data reveal that amyloid fibrils possess intrinsic photonic activity, showing luminescence over a wide range of the electromagnetic spectrum from the ultraviolet to the near-infrared.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:liu:diva-158956 (URN)10.1038/s41566-019-0471-x (DOI)000472545400009 ()
Available from: 2019-07-19 Created: 2019-07-19 Last updated: 2019-08-12Bibliographically approved
Schuetz, A. K., Hornemann, S., Waelti, M. A., Greuter, L., Tiberi, C., Cadalbert, R., . . . Meier, B. H. (2018). Binding of Polythiophenes to Amyloids: Structural Mapping of the Pharmacophore. ACS Chemical Neuroscience, 9(3), 475-481
Open this publication in new window or tab >>Binding of Polythiophenes to Amyloids: Structural Mapping of the Pharmacophore
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2018 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 9, no 3, p. 475-481Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
Keywords
Amyloid; pharmacophore; luminescent conjugated polythiophenes; diagnostic marker; fluorescence; solid-state NMR
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-147430 (URN)10.1021/acschemneuro.7b00397 (DOI)000428356500012 ()29178774 (PubMedID)2-s2.0-85037681655 (Scopus ID)
Note

Funding Agencies|Swiss National Science Foundation [200020_159707, 200020_146757, 200020_147660]; French ANR [ANR-14-CE09-0024B]; European Research Council [ERC: 670958]

Available from: 2018-05-17 Created: 2018-05-17 Last updated: 2018-05-22Bibliographically approved
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
Nilsson, P., Lindgren, M. & Hammarström, P. (2018). Luminescent-Conjugated Oligothiophene Probe Applications for Fluorescence Imaging of Pure Amyloid Fibrils and Protein Aggregates in Tissues. In: Einar M. Sigurdsson, Miguel Calero and María Gasset (Ed.), Amyloid Proteins: Methods and Protocols (pp. 485-496). Humana Press, 1779
Open this publication in new window or tab >>Luminescent-Conjugated Oligothiophene Probe Applications for Fluorescence Imaging of Pure Amyloid Fibrils and Protein Aggregates in Tissues
2018 (English)In: Amyloid Proteins: Methods and Protocols / [ed] Einar M. Sigurdsson, Miguel Calero and María Gasset, Humana Press, 2018, Vol. 1779, p. 485-496Chapter in book (Refereed)
Abstract [en]

Luminescent-conjugated oligo- and polythiophenes (LCOs and LCPs) are valuable tools for optical imaging of a plethora of protein aggregates associated with amyloidoses. Here, we outline updated protocols for the application of the anionic pentameric LCO, p-FTAA, for staining and hyperspectral imaging of protein aggregates in a variety of settings such as in vitro formed amyloid fibrils, ex vivo tissue sections, and whole brain Drosophila.

Place, publisher, year, edition, pages
Humana Press, 2018
Series
Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029 ; 1779
Keywords
Amyloid; Fluorescence imaging; Luminescent-conjugated oligothiophenes; Protein aggregates; p-FTAA
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:liu:diva-152516 (URN)10.1007/978-1-4939-7816-8_30 (DOI)29886552 (PubMedID)9781493978151 (ISBN)9781493978168 (ISBN)
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-03-29
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
Nordeman, P., Johansson, L. B. G., Bäck, M., Estrada, S., Hall, H., Sjölander, D., . . . Antoni, G. (2016). 11C and 18FRadiolabeling of Tetra- and Pentathiophenes as PET-ligands for Amyloid Protein Aggregates. ACS Medicinal Chemistry Letters, 7(4), 368-373
Open this publication in new window or tab >>11C and 18FRadiolabeling of Tetra- and Pentathiophenes as PET-ligands for Amyloid Protein Aggregates
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2016 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 7, no 4, p. 368-373Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
National Category
Chemical Sciences Cell Biology
Identifiers
urn:nbn:se:liu:diva-122273 (URN)10.1021/acsmedchemlett.5b00309 (DOI)000374436700007 ()
Note

Funding agencies:  Swedish Research Council; Swedish Foundation for Strategic Research; LiU-Neuro; Ehrling-Persson Foundation; Goran-Gustafsson Foundation; ERC Starting Independent Researcher grant (Project: MUMID)

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Available from: 2015-10-27 Created: 2015-10-27 Last updated: 2018-04-25Bibliographically approved
Babu Moparthi, S., Carlsson, U., Vincentelli, R., Jonsson, B.-H., Hammarström, P. & Wenger, J. (2016). Differential conformational modulations of MreB folding upon interactions with GroEL/ES and TRiC chaperonin components. Scientific Reports, 6(28386)
Open this publication in new window or tab >>Differential conformational modulations of MreB folding upon interactions with GroEL/ES and TRiC chaperonin components
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 28386Article in journal (Refereed) Published
Abstract [en]

Here, we study and compare the mechanisms of action of the GroEL/GroES and the TRiC chaperonin systems on MreB client protein variants extracted from E. coli. MreB is a homologue to actin in prokaryotes. Single-molecule fluorescence correlation spectroscopy (FCS) and time-resolved fluorescence polarization anisotropy report the binding interaction of folding MreB with GroEL, GroES and TRiC. Fluorescence resonance energy transfer (FRET) measurements on MreB variants quantified molecular distance changes occurring during conformational rearrangements within folding MreB bound to chaperonins. We observed that the MreB structure is rearranged by a binding-induced expansion mechanism in TRiC, GroEL and GroES. These results are quantitatively comparable to the structural rearrangements found during the interaction of beta-actin with GroEL and TRiC, indicating that the mechanism of chaperonins is conserved during evolution. The chaperonin-bound MreB is also significantly compacted after addition of AMP-PNP for both the GroEL/ES and TRiC systems. Most importantly, our results showed that GroES may act as an unfoldase by inducing a dramatic initial expansion of MreB (even more than for GroEL) implicating a role for MreB folding, allowing us to suggest a delivery mechanism for GroES to GroEL in prokaryotes.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Biophysics
Identifiers
urn:nbn:se:liu:diva-130280 (URN)10.1038/srep28386 (DOI)000378228700001 ()27328749 (PubMedID)
Note

Funding Agencies|European Commission [FP7-ICT-2011-7, ERC StG 278242]; Goran Gustafsson Foundation; Swedish Alzheimer Foundation

Available from: 2016-08-01 Created: 2016-07-28 Last updated: 2018-04-25
Sjölander, D., Roecken, C., Westermark, P., Westermark, G. T., Nilsson, P. & Hammarström, P. (2016). Establishing the fluorescent amyloid ligand h-FTAA for studying human tissues with systemic and localized amyloid. Amyloid: Journal of Protein Folding Disorders, 23(2), 98-108
Open this publication in new window or tab >>Establishing the fluorescent amyloid ligand h-FTAA for studying human tissues with systemic and localized amyloid
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2016 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 23, no 2, p. 98-108Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2016
Keywords
Amyloidosis; Congo red; diagnosis; fluorescence; microscopy; oligothiophenes; screening
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-128924 (URN)10.3109/13506129.2016.1158159 (DOI)000375905000004 ()26987044 (PubMedID)
Note

Funding Agencies|Swedish Foundation for Strategic Research; Swedish Research Council; Goran Gustafsson Foundation; Linkoping University Center of Neuroscience; European Research Council (ERC starting grant; Project MUMID); EU-FP7 Health programme project LUPAS; Selanders Foundation; patients association FAM; patients association FAMY Norrbotten; patients association Amyl

Available from: 2016-06-09 Created: 2016-06-07 Last updated: 2018-09-26
Campos Melo, R. I., Wu, X., Elgland, M., Konradsson, P. & Hammarström, P. (2016). Novel Trans-Stilbene-based Fluorophores as Probes for Spectral Discrimination of Native and Protofibrillar Transthyretin. ACS Chemical Neuroscience, 7(7), 924-940
Open this publication in new window or tab >>Novel Trans-Stilbene-based Fluorophores as Probes for Spectral Discrimination of Native and Protofibrillar Transthyretin
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2016 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 7, no 7, p. 924-940Article in journal (Refereed) Published
Abstract [en]

Accumulation of misfolded transthyretin (TTR) as amyloid fibrils causes various human disorders. Native transthyretin is a neurotrophic protein and is a putative extracellular molecular chaperone. Several fluorophores have been shown in vitro to bind selectively to native TTR. Other compounds, such as thioflavin T, bind TTR amyloid fibrils. The probe 1-anilinonaphthalene-8-sulfonate (ANS) binds to both native and fibrillar TTR, becoming highly fluorescent, but with indistinguishable emission spectra for native and fibrillar TTR. Herein we report our efforts to develop a fluorescent small molecule capable of binding both native and misfolded protofibrillar TTR, providing distinguishable emission spectra. We used microwave synthesis for efficient production of a small library of trans-stilbenes and fluorescence spectral screening of their binding properties. We synthesized and tested 22 trans-stilbenes displaying a variety of functional groups. We successfully developed two naphthyl-based trans-stilbenes probes that detect both TTR states at physiological concentrations. The compounds bound with nanomolar to micromolar affinities and displayed distinct emission maxima upon binding native or misfolded protofibrillar TTR (>100 nm difference). The probes were mainly responsive to environment polarity providing evidence for the divergent hydrophobic structure of the binding sites of these protein conformational states. Furthermore, we were able to successfully use one of these probes to quantify the relative amounts of native and protofibrillar TTR in a dynamic equilibrium. In conclusion, we identified two trans-stilbene-based fluorescent probes, (E)-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol (11) and (E)-4-(2-(naphthalen-2-yl)vinyl)benzene-1,2-diol (14), that bind native and protofibrillar TTR, providing a wide difference in emission maxima allowing conformational discrimination by fluorescence spectroscopy. We expect these novel molecules to serve as important chemical biology research tools in studies of TTR folding and misfolding.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
Keywords
transthyretin, amyloid, stilbene, fluorescence, probe, spectrum
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-122842 (URN)10.1021/acschemneuro.6b00062 (DOI)000380297500009 ()27144293 (PubMedID)
Note

At the time for thesis presentation publication was in status: Manuscript

Funding agencies:The work was supported by Goran Gustafsson's Foundation (PH), The Swedish Research Council (PH), The Linkoping center for systemic neuroscience, LiU-Neuro, (XW), and Sven and Lilly Lawski's foundation (ME).

Available from: 2015-11-26 Created: 2015-11-26 Last updated: 2018-04-25Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-5827-3587

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