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Åslund, Andreas
Alternative names
Publications (10 of 22) Show all publications
Johansson, L. B. G., Simon, R., Bergström, G., Eriksson, M., Prokop, S., Mandenius, C.-F., . . . Nilsson, P. (2015). An azide functionalized oligothiophene ligand - A versatile tool for multimodal detection of disease associated protein aggregates. Biosensors & bioelectronics, 63, 204-211
Open this publication in new window or tab >>An azide functionalized oligothiophene ligand - A versatile tool for multimodal detection of disease associated protein aggregates
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2015 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 63, p. 204-211Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Protein aggregates; Oligothiophene; Fluorescence; Surface plasmon resonance; Click chemistry
National Category
Chemical Sciences Biological Sciences
Identifiers
urn:nbn:se:liu:diva-112169 (URN)10.1016/j.bios.2014.07.042 (DOI)000343337000030 ()25089818 (PubMedID)
Note

Funding Agencies|Swedish Foundation for Strategic Research; Ehrling Persson Foundation; ERC Starting Independent Researcher grant (Project: MUMID)

Available from: 2014-11-18 Created: 2014-11-18 Last updated: 2019-01-22
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
Simon, R., Shirani, H., Åslund, K. O., Bäck, M., Haroutunian, V., Gandy, S. & Nilsson, P. R. (2014). Pentameric Thiophene-Based Ligands that Spectrally Discriminate Amyloid-b and Tau Aggregates Display Distinct Solvatochromism and Viscosity-Induced Spectral Shifts. Chemistry - A European Journal, 20(39), 12537-12543
Open this publication in new window or tab >>Pentameric Thiophene-Based Ligands that Spectrally Discriminate Amyloid-b and Tau Aggregates Display Distinct Solvatochromism and Viscosity-Induced Spectral Shifts
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2014 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 39, p. 12537-12543Article in journal (Refereed) Published
Abstract [en]

A wide range of neurodegenerative diseases are characterized by the deposition of multiple protein aggregates. Ligands for molecular characterization and discrimination of these pathological hallmarks are thus important for understanding their potential role in pathogenesis as well as for clinical diagnosis of the disease. In this regard, luminescent conjugated oligothiophenes (LCOs) have proven useful for spectral discrimination of amyloid-beta (Aβ) and tau neurofibrillary tangles (NFTs), two of the pathological hallmarks associated with Alzheimer’s disease. Herein, the solvatochromism of a library of anionic pentameric thiophene-based ligands, as well as their ability to spectrally discriminate Aβ and tau aggregates, were investigated. Overall, the results from this study identified distinct solvatochromic and viscosity-dependent behavior of thiophene-based ligands that can be applied as indices to direct the chemical design of improved LCOs for spectral separation of Aβ and tau aggregates in brain tissue sections. The results also suggest that the observed spectral transitions of the ligands are due to their ability to conform by induced fit to specific microenvironments within the binding interface of each particular protein aggregate. We foresee that these findings might aid in the chemical design of thiophene-based ligands that are increasingly selective for distinct disease-associated protein aggregates.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2014
Keywords
fluorescence; imaging agents; luminescent conjugated oligothiophenes; protein aggregates; solvatochromism
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-111655 (URN)10.1002/chem.201402890 (DOI)000342626200026 ()25111601 (PubMedID)
Available from: 2014-10-28 Created: 2014-10-28 Last updated: 2017-12-05Bibliographically approved
Arja, K., Sjölander, D., Åslund, A., Prokop, S., Heppner, F. L., Konradsson, P., . . . Nilsson, P. (2013). Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand. Macromolecular rapid communications, 34(9), 723-730
Open this publication in new window or tab >>Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand
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2013 (English)In: Macromolecular rapid communications, ISSN 1022-1336, E-ISSN 1521-3927, Vol. 34, no 9, p. 723-730Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Wiley-VCH Verlag, 2013
Keywords
oligothiophene, porphyrin, protein deposits, imaging, fluorescence
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-93385 (URN)10.1002/marc.201200817 (DOI)000318354500004 ()
Note

Funding Agencies|Swedish Research Council||Knut and Alice Wallenberg Foundation||Swedish Foundation for Strategic Research||European Union FP7 HEALTH (Project LUPAS)||LiU Neuroscience Center||ERC Starting Independent Researcher grant (Project: MUMID)||

Available from: 2013-05-31 Created: 2013-05-31 Last updated: 2018-08-24
Heilbronner, G., Eisele, Y. S., Langer, F., Kaeser, S. A., Novotny, R., Nagarathinam, A., . . . Jucker, M. (2013). Seeded strain-like transmission of beta-amyloid morphotypes in APP transgenic mice. EMBO Reports, 14(11), 1017-1022
Open this publication in new window or tab >>Seeded strain-like transmission of beta-amyloid morphotypes in APP transgenic mice
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2013 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 14, no 11, p. 1017-1022Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND, 2013
Keywords
Alzheimer, amyloid, protein aggregation, prion strain
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-102076 (URN)10.1038/embor.2013.137 (DOI)000326389600014 ()
Note

Funding Agencies|BMBF (ERA-Net NEURON-MIPROTRAN)||European Union FP7 HEALTH (LUPAS)||Swedish Foundation for Strategic Research (SSF)||ERC||

Available from: 2013-12-03 Created: 2013-11-29 Last updated: 2018-04-25
Klingstedt, T., Shirani, H., Åslund, A., Cairns, N. J., Sigurdson, C. J., Goedert, M. & Nilsson, P. (2013). The Structural Basis for Optimal Performance of Oligothiophene-Based Fluorescent Amyloid Ligands: Conformational Flexibility is Essential for Spectral Assignment of a Diversity of Protein Aggregates. Chemistry - A European Journal, 19(31), 10179-10192
Open this publication in new window or tab >>The Structural Basis for Optimal Performance of Oligothiophene-Based Fluorescent Amyloid Ligands: Conformational Flexibility is Essential for Spectral Assignment of a Diversity of Protein Aggregates
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2013 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 31, p. 10179-10192Article in journal (Refereed) Published
Abstract [en]

Protein misfolding diseases are characterized by deposition of protein aggregates, and optical ligands for molecular characterization of these disease-associated structures are important for understanding their potential role in the pathogenesis of the disease. Luminescent conjugated oligothiophenes (LCOs) have proven useful for optical identification of a broader subset of disease-associated protein aggregates than conventional ligands, such as thioflavin T and Congo red. Herein, the molecular requirements for achieving LCOs able to detect nonthioflavinophilic Aβ aggregates or non-congophilic prion aggregates, as well as spectrally discriminate Aβ and tau aggregates, were investigated. An anionic pentameric LCO was subjected to chemical engineering by: 1) replacing thiophene units with selenophene or phenylene moieties, or 2) alternating the anionic substituents along the thiophene backbone. In addition, two asymmetric tetrameric ligands were generated. Overall, the results from this study identified conformational freedom and extended conjugation of the conjugated backbone as crucial determinants for obtaining superior thiophene-based optical ligands for sensitive detection and spectral assignment of disease-associated protein aggregates.

Place, publisher, year, edition, pages
Wiley-VCH Verlag, 2013
Keywords
Alzheimers disease, fluorescent probes, luminescent conjugated oligothiophenes, microscopy, protein folding
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-96708 (URN)10.1002/chem.201301463 (DOI)000321983700020 ()
Note

Funding Agencies|Swedish Foundation for Strategic Research||European Research Council||NIH|P50AG056815PO1-AG03991|

Available from: 2013-08-23 Created: 2013-08-23 Last updated: 2017-12-06
Margalith, I., Suter, C., Ballmer, B., Schwarz, P., Tiberi, C., Sonati, T., . . . Aguzzi, A. (2012). Polythiophenes Inhibit Prion Propagation by Stabilizing Prion Protein (PrP) Aggregates. Journal of Biological Chemistry, 287(23), 18872-18887
Open this publication in new window or tab >>Polythiophenes Inhibit Prion Propagation by Stabilizing Prion Protein (PrP) Aggregates
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2012 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 23, p. 18872-18887Article in journal (Refereed) Published
Abstract [en]

Luminescent conjugated polymers (LCPs) interact with ordered protein aggregates and sensitively detect amyloids of many different proteins, suggesting that they may possess antiprion properties. Here, we show that a variety of anionic, cationic, and zwitterionic LCPs reduced the infectivity of prion-containing brain homogenates and of prion-infected cerebellar organotypic cultured slices and decreased the amount of scrapie isoform of PrPC (PrPSc) oligomers that could be captured in an avidity assay. Paradoxically, treatment enhanced the resistance of PrPSc to proteolysis, triggered the compaction, and enhanced the resistance to proteolysis of recombinant mouse PrP(23-231) fibers. These results suggest that LCPs act as antiprion agents by transitioning PrP aggregates into structures with reduced frangibility. Moreover, ELISA on cerebellar organotypic cultured slices and in vitro conversion assays with mouse PrP(23-231) indicated that poly(thiophene-3-acetic acid) may additionally interfere with the generation of PrPSc by stabilizing the conformation of PrPC or of a transition intermediate. Therefore, LCPs represent a novel class of antiprion agents whose mode of action appears to rely on hyperstabilization, rather than destabilization, of PrPSc deposits.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2012
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-79639 (URN)10.1074/jbc.M112.355958 (DOI)000306411900001 ()
Note

Funding Agencies|European Union P-7 Health||Swiss National Foundation||Novartis Research Foundation||European Research Council||Swedish Foundation for Strategic Research|FFL-4|

Available from: 2012-08-13 Created: 2012-08-13 Last updated: 2019-11-08
Klingstedt, T., Åslund, A., Simon, R., Johansson, L. B. G., Mason, J., Nyström, S., . . . Nilsson, P. (2011). Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates. Organic and biomolecular chemistry, 9(24), 8356-8370
Open this publication in new window or tab >>Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates
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2011 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 9, no 24, p. 8356-8370Article in journal (Refereed) Published
Abstract [en]

Molecular probes for selective identification of protein aggregates are important to advance our understanding of the molecular pathogenesis underlying protein aggregation diseases. Here we report the chemical design of a library of anionic luminescent conjugated oligothiophenes (LCOs), which can be utilized as ligands for detection of protein aggregates. Certain molecular requirements were shown to be necessary for detecting (i) early non-thioflavinophilic protein assemblies of A beta 1-42 and insulin preceding the formation of amyloid fibrils and (ii) for obtaining distinct spectral signatures of the two main pathological hallmarks observed in human Alzheimers diease brain tissue (A beta plaques and neurofibrillary tangles). Our findings suggest that a superior anionic LCO-based ligand should have a backbone consisting of five to seven thiophene units and carboxyl groups extending the conjugated thiophene backbone. Such LCOs will be highly useful for studying the underlying molecular events of protein aggregation diseases and could also be utilized for the development of novel diagnostic tools for these diseases.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2011
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-73487 (URN)10.1039/c1ob05637a (DOI)000297354100019 ()
Available from: 2012-01-04 Created: 2012-01-04 Last updated: 2019-11-08
Hammarström, P., Simon, R., Nyström, S., Konradsson, P., Åslund, A. & Nilsson, P. (2010). A Fluorescent Pentameric Thiophene Derivative Detects in Vitro-Formed Prefibrillar Protein Aggregates. BIOCHEMISTRY, 49(32), 6838-6845
Open this publication in new window or tab >>A Fluorescent Pentameric Thiophene Derivative Detects in Vitro-Formed Prefibrillar Protein Aggregates
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2010 (English)In: BIOCHEMISTRY, ISSN 0006-2960, Vol. 49, no 32, p. 6838-6845Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
ACS American Chemical Society, 2010
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-58657 (URN)10.1021/bi100922r (DOI)000280668000003 ()
Available from: 2010-08-22 Created: 2010-08-20 Last updated: 2019-11-08
Lindgren, M., Glimsdal, E., Åslund, A., Simon, R., Hammarström, P. & Nilsson, P. (2010). Luminescence and two-photon absorption cross section of novel oligomeric luminescent conjugated polythiophenes for diagnostics of amyloid fibrils. Nonlinear Optics Quantum Optics, 40(1-4), 241-251
Open this publication in new window or tab >>Luminescence and two-photon absorption cross section of novel oligomeric luminescent conjugated polythiophenes for diagnostics of amyloid fibrils
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2010 (English)In: Nonlinear Optics Quantum Optics, ISSN 1543-0537, Vol. 40, no 1-4, p. 241-251Article in journal (Refereed) Published
Abstract [en]

Here we present the TPA cross section and quantum efficiencies of a series of novel oligomeric luminescent conjugated polythiophenes used for detection and spectral diagnostics of amyloid protein aggregates of the amyloid-beta peptide associated with Alzheimers disease. Specifically, these probes consist of pentameric or heptameric thiophenes derivatives with carboxylic substituents attached onto various thiophene rings. The probes absorbs over a broad range approx. 400-500 nm with quantum efficiency of approx. 20% in at neutral pH conditions, and also showed TPA cross sections of 5-50 GM in the range 700-840 nm, in the same order of magnitude as commonly used fluorescein derivatives. Importantly, the multiphoton excitation capabilities of LCPs provided excellent performance when compared to imaging using conventional "single photon" excitation. It is also demonstrated their utilization in both one-and two-photon excitation laser scanning microscope spectral imaging for diagnostics of Alzheimer disease pathology in ex vivo histological sections.

Place, publisher, year, edition, pages
Old City Publishing Inc, 2010
Keywords
Amyloid detection; Amyloid spectroscopic diagnostics; Fluorescent dyes; Quantum efficiency; Thiophene oligomers; TPA cross section
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-57014 (URN)
Available from: 2010-06-14 Created: 2010-06-09 Last updated: 2018-04-25
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