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Pentameric Thiophene-Based Ligands that Spectrally Discriminate Amyloid-b and Tau Aggregates Display Distinct Solvatochromism and Viscosity-Induced Spectral Shifts
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
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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. Vol. 20, no 39, 12537-12543 p.
Keyword [en]
fluorescence; imaging agents; luminescent conjugated oligothiophenes; protein aggregates; solvatochromism
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:liu:diva-111655DOI: 10.1002/chem.201402890ISI: 000342626200026PubMedID: 25111601OAI: oai:DiVA.org:liu-111655DiVA: diva2:758671
Available from: 2014-10-28 Created: 2014-10-28 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Anionic oligothiophenes: Optical tools for multimodal fluorescent assignment of protein aggregates
Open this publication in new window or tab >>Anionic oligothiophenes: Optical tools for multimodal fluorescent assignment of protein aggregates
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:nbn:se:liu:diva-111657 (URN)978-91-7519-205-5 (ISBN)
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

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Simon, RozalynShirani, HamidÅslund, K. O. AndreasBäck, MarcusNilsson, Peter R

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