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Novel Pentameric Thiophene Derivatives for in Vitro and in Vivo Optical Imaging of a Plethora of Protein Aggregates in Cerebral Amyloidoses
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
Institute of Neuropathology, Department of Pathology, Universitätsspital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, D-72076 Tuebingen, Germany.
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2009 (English)In: ACS CHEMICAL BIOLOGY, ISSN 1554-8929, Vol. 4, no 8, 673-684 p.Article 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 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.

Place, publisher, year, edition, pages
2009. Vol. 4, no 8, 673-684 p.
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-20420DOI: 10.1021/cb900112vOAI: oai:DiVA.org:liu-20420DiVA: diva2:234531
Available from: 2009-09-08 Created: 2009-09-07 Last updated: 2015-05-28
In thesis
1. Designing thiophene-based fluorescent probes for the study of neurodegenerative protein aggregation diseases: From test tube to in vivo experiments
Open this publication in new window or tab >>Designing thiophene-based fluorescent probes for the study of neurodegenerative protein aggregation diseases: From test tube to in vivo experiments
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Protein aggregation is an event related to numerous neurodegenerative diseases, such as Alzhemier’s disease and prion diseases. However little is known as to how and why the aggregates form and furthermore, the toxic specie may not be the mature fibril but an on route or off route specie towards mature aggregates. During this project molecular probes were synthesized that may shed some light to these questions. The probes are thiophene based and the technique used for detection was mainly fluorescence. It was shown that the previously established thiophene based in vitro staining technique is valid ex vivo and in vivo. This would not have been possible without the synthesis of a variety of functionalized polymeric thiophene based probes; their in vitro and ex vivo staining properties were taken into consideration when the design of the small oligomeric probes were decided upon. These probes were shown to spectrally distinguish different types of amyloid, pass the bloodbrain barrier within minutes and specifically and selectively stain protein aggregates in the brains of mice.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 68 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1286
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-51731 (URN)978-91-7393-496-1 (ISBN)
Public defence
2009-12-17, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 13:15 (English)
Opponent
Supervisors
Available from: 2009-11-16 Created: 2009-11-16 Last updated: 2009-11-17Bibliographically approved
2. Fluorescent thiophene-based ligands for detection and characterization of disease-associated protein aggregates
Open this publication in new window or tab >>Fluorescent thiophene-based ligands for detection and characterization of disease-associated protein aggregates
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis the unique optical properties of fluorescent ligands termed luminescent conjugated oligothiophenes (LCOs) have been used to study a variety of protein aggregates associated with human protein misfolding disease. This heterogeneous group of diseases contains well known and fatal members such as Alzheimer´s and Huntington´s disease and the development of sensitive tools for the detection and characterization of protein aggregates is crucial for unravelling the complexity of these pathologies. Conventionally, the molecular dyes Congo red and thioflavin T (ThT) have been the primary choices for detecting and monitoring protein misfolding events. However, the rigid scaffold of both Congo red and ThT only offers an on or off mode and limits their ability to make fine distinctions at the molecular level. In contrast, LCOs have a flexible conjugated backbone and in addition to detect a broader subset of misfolded proteins, LCO can be used to visualize the heterogeneity of protein aggregates.

The work presented in this thesis has given novel insights regarding the close connection between LCO design and optical performance. By altering the backbone length and the arrangement of substituents as well as replacing thiophene units with moieties affecting conjugation length and conformational freedom, the structural requirements of an optimal LCO for a certain application have been revealed. LCOs having a pentameric thiophene backbone with carboxyl end-groups were able to i) cross the blood-brain barrier and selectively stain cerebral amyloid β (Aβ) plaques, ii) detect non-thioflavinophilic Aβ aggregates and non-congophilic prion aggregates, iii) spectrally discriminate Aβ from tau aggregates and iiii) strongly label protein inclusion bodies. However, in some applications this design was outdone by others and in general, the conjugation length and the level of conformational freedom of the backbone were important determinants of the performance of the LCO.

Overall, the findings in this thesis illustrate how small alterations in the LCO molecular scaffold may have large impact on the ligand properties. The results highlight the importance of having a toolbox of diverse ligands in order to increase our knowledge regarding the complex nature of protein aggregates.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 81 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1518
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-92772 (URN)978-91-7519-623-7 (ISBN)
Public defence
2013-05-31, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 10:15 (Swedish)
Opponent
Supervisors
Available from: 2013-05-21 Created: 2013-05-21 Last updated: 2014-04-08Bibliographically approved

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Åslund, AndreasKlingstedt, TheréseKonradsson, PeterHammarström, PerNilsson, Peter

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