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Designing thiophene-based fluorescent probes for the study of neurodegenerative protein aggregation diseases: From test tube to in vivo experiments
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
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: urn:nbn:se:liu:diva-51731ISBN: 978-91-7393-496-1 (print)OAI: oai:DiVA.org:liu-51731DiVA: diva2:277179
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
List of papers
1. Imaging distinct conformational states of amyloid-β fibrils in Alzheimer's disease using novel luminescent probes
Open this publication in new window or tab >>Imaging distinct conformational states of amyloid-β fibrils in Alzheimer's disease using novel luminescent probes
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2007 (English)In: ACS Chemical Biology, ISSN 1554-8929, Vol. 2, no 8, 553-560 p.Article in journal (Refereed) Published
Abstract [en]

Using luminescent conjugated polyelectrolyte probes (LCPs), we demonstrate the possibility to distinguish amyloid-β 1-42 peptide (Aβ1-42) fibril conformations, by analyzing in vitro generated amyloid fibrils of Aβ1-42 formed under quiescent and agitated conditions. LCPs were then shown to resolve such conformational heterogeneity of amyloid deposits in vivo. A diversity of amyloid deposits depending upon morphology and anatomic location was illustrated with LCPs in frozen ex vivo brain sections from a transgenic mouse model (tg-APPswe) of Alzheimer's disease. Comparative LCP fluorescence showed that compact-core plaques of amyloid β precursor protein transgenic mice were composed of rigid dense amyloid. A more abundant form of amyloid plaque displayed morphology of a compact center with a protruding diffuse exterior. Surprisingly, the compact center of these plaques showed disordered conformations of the fibrils, and the exterior was composed of rigid amyloid protruding from the disordered center. This type of plaque appears to grow from more loosely assembled regions toward solidified amyloid tentacles. This work demonstrates how application of LCPs can prove helpful to monitor aggregate structure of in vivo formed amyloid deposits such as architecture, maturity, and origin.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-40622 (URN)10.1021/cb700116u (DOI)53662 (Local ID)53662 (Archive number)53662 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2014-04-08
2. Studies of luminescent conjugated polythiophene derivatives-Enhanced spectral discrimination of protein conformational states
Open this publication in new window or tab >>Studies of luminescent conjugated polythiophene derivatives-Enhanced spectral discrimination of protein conformational states
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2007 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 18, no 6, 1860-1868 p.Article in journal (Refereed) Published
Abstract [en]

Improved probes for amyloid fibril formation are advantageous for the early detection and better understanding of this disease-associated process. Here, we report a comparative study of eight luminescent conjugated polythiophene derivates (LCPs) and their discrimination of a protein (insulin) in the native or amyloid-like fibrillar state. For two of the LCPs, the synthesis is reported. Compared to their monomer-based analogues, trimer-based LCPs showed significantly better optical signal specificity for amyloid-like fibrils, seen from increased quantum yield and spectral shift. The trimer-based LCPs alone were highly quenched and showed little interaction with native insulin, as seen from analytical ultracentrifugation and insignificant spectral differences from the trimer-based LCP in buffered and native protein solution. Hence, the trimer-based LCPs showed enhanced discrimination between the amyloid-like fibrillar state and the corresponding native protein.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-14600 (URN)10.1021/bc700180g (DOI)
Available from: 2007-10-12 Created: 2007-10-12 Last updated: 2017-12-13
3. Novel Pentameric Thiophene Derivatives for in Vitro and in Vivo Optical Imaging of a Plethora of Protein Aggregates in Cerebral Amyloidoses
Open this publication in new window or tab >>Novel Pentameric Thiophene Derivatives for in Vitro and in Vivo Optical Imaging of a Plethora of Protein Aggregates in Cerebral Amyloidoses
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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.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-20420 (URN)10.1021/cb900112v (DOI)
Available from: 2009-09-08 Created: 2009-09-07 Last updated: 2015-05-28

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