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Anionic oligothiophenes: Optical tools for multimodal fluorescent assignment of protein aggregates
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Luminescent conjugated oligothiophenes (LCOs) represent a useful and interesting class of materials well known for their abilities as transducers for colorimetric and fluorometric reporting. Specifically, they have the ability to produce a conformation-dependent spectral signature reflective of changes in their local environment.  This physical property makes conjugated polymers an indispensible tool in the toolbox of fluorescent reporters used for distinguishing protein aggregates. Because fluorescence measurements provide a number of parameters for observing changes within a system (e.g., changes in intensity, wavelength, energy transfer, and emission lifetime), the coupling of such measurements with the unique fluorescence reporting capabilities of LCOs has been successful in a number of biological systems. The Nilsson group has demonstrated the use of both polydisperse and monodisperse conjugated polythiophenes for the purpose of amyloid protein aggregate detection both in vitro and ex vivo. My doctoral studies have included synthesis and the photophysical evaluation of pentameric substituted oligothiophenes for utilization as molecular probes for investigating the structure and conformation of amyloid protein aggregates. Through the synthesis of a library of pentameric probes with variations in side-chain substituents, we have studied the effects of pH, solvent, and viscosity on probe behavior and spectral shifts to elucidate the role of chemical structure on probe performance. Through a clearer understanding of the nature of LCOs and their individual chromic responses, we hope to provide researchers and clinicians additional tools for investigating and “bringing to light” the multifaceted nature of amyloids.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. , 41 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1630
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:liu:diva-111657ISBN: 978-91-7519-205-5 (print)OAI: oai:DiVA.org:liu-111657DiVA: diva2:758719
Public defence
2014-11-14, Visionen B-huset, Campus Valla, Linköpings universitet, Linköping, 09:15 (English)
Opponent
Supervisors
Available from: 2014-10-28 Created: 2014-10-28 Last updated: 2014-10-28Bibliographically approved
List of papers
1. A Fluorescent Pentameric Thiophene Derivative Detects in Vitro-Formed Prefibrillar Protein Aggregates
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, 6838-6845 p.Article 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: 2015-05-28
2. Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates
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, 8356-8370 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 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: 2017-12-08
3. Pentameric Thiophene-Based Ligands that Spectrally Discriminate Amyloid-b and Tau Aggregates Display Distinct Solvatochromism and Viscosity-Induced Spectral Shifts
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, 12537-12543 p.Article 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
Keyword
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
4. pH-dependent optical transitions in anionic pentameric oligothiophenes
Open this publication in new window or tab >>pH-dependent optical transitions in anionic pentameric oligothiophenes
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2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Understanding the photo-physical processes in fluorescent probes are essential as such dyes are widely utilized in molecular biology. Here we report the pH-dependent optical transitions of a library of anionic pentameric luminescent conjugated oligothiophenes (LCOs) that have been used for fluorescent identification of protein aggregates, the pathological hallmark of many devastating diseases. Absorption-, excitation- and emission spectra were recorded for all LCOs in different buffers with a pH range from 3.5 to 7. p-FTAA, a LCO having a central core consisting of a trimeric thiophene  building block with head-to-head acetic acid functionalization as well as terminal carboxyl groups extending the pentameric thiophene backbone, displayed pH/dependent optical characteristics correlating to a non-planar to planar transition of the conjugated backbone as well as aggregation between adjacent thiophene chain upon protonation of the  acetic acid side chains. In contrast, chemically related analogues to p-FTAA lacking the  terminal carboxyl groups extending the pentameric thiophene backbone or the conformational ability to undergo a non/planar to planar transition of the  conjugated backbone, displayed different optical characteristics compared to p-FTAA. Overall these studies highlighted that minor chemical alteration of LCOs can result in major difference in the optical characteristics obtained from the dyes and the results might aid in designing novel LCOs that have  superior optical performance as amyloid ligands.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-111656 (URN)
Available from: 2014-10-28 Created: 2014-10-28 Last updated: 2014-10-28Bibliographically approved
5. Multimodal fluorescene microscopy of prion strain specific PrP deposits stained by thiophene-bassed amyloid ligands
Open this publication in new window or tab >>Multimodal fluorescene microscopy of prion strain specific PrP deposits stained by thiophene-bassed amyloid ligands
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2014 (English)In: Prion, ISSN 1933-6896, E-ISSN 1933-690X, Vol. 8, no 4, 319-329 p.Article in journal (Refereed) Published
Abstract [en]

The disease-associated prion protein (PrP) forms aggregates which vary in structural conformation yet share identical primary sequence. These variations in PrP conformation are believed to manifest in prion strains exhibiting distinctly different periods of disease incubation as well as regionally specific aggregate deposition within the brain. The anionic luminescent conjugated polythiophene (LCP), polythiophene acetic acid (PTAA) has previously been used to distinguish PrP deposits associated with distinct mouse adapted strains via distinct fluorescence emission profiles from the dye. Here we employed PTAA and 3 structurally related chemically defined luminescent conjugated oligothiophenes (LCOs) to stain brain tissue sections from mice inoculated with 2 distinct prion strains. Our results showed that in addition to emission spectra, excitation, and fluorescence lifetime imaging microscopy (FLIM) can fruitfully be assessed for optical distinction of PrP deposits associated with distinct prion strains. Our findings support the theory that alterations in LCP/LCO fluorescence are due to distinct conformational restriction of the thiophene backbone upon interaction with PrP aggregates associated with distinct prion strains. We foresee that LCP and LCO staining in combination with multimodal fluorescence microscopy might aid in detecting structural differences among discrete protein aggregates and in linking protein conformational features with disease phenotypes for a variety of neurodegenerative proteinopathies.

Place, publisher, year, edition, pages
Taylor & Francis, 2014
National Category
Chemical Sciences Natural Sciences
Identifiers
urn:nbn:se:liu:diva-106792 (URN)10.4161/pri.29239 (DOI)000348376000006 ()
Available from: 2014-05-23 Created: 2014-05-23 Last updated: 2017-12-05Bibliographically approved

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