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Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand
Linköpings universitet, Institutionen för fysik, kemi och biologi, Organisk Kemi. Linköpings universitet, Tekniska högskolan. Linköping, .
Linköpings universitet, Institutionen för fysik, kemi och biologi, Proteinkemi. Linköpings universitet, Tekniska fakulteten. Linköping, .
Linköpings universitet, Institutionen för fysik, kemi och biologi, Organisk Kemi. Linköpings universitet, Tekniska fakulteten. Linköping, .
Charite, Germany .
Vise andre og tillknytning
2013 (engelsk)Inngår i: Macromolecular rapid communications, ISSN 1022-1336, E-ISSN 1521-3927, Vol. 34, nr 9, s. 723-730Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Wiley-VCH Verlag , 2013. Vol. 34, nr 9, s. 723-730
Emneord [en]
oligothiophene, porphyrin, protein deposits, imaging, fluorescence
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-93385DOI: 10.1002/marc.201200817ISI: 000318354500004OAI: oai:DiVA.org:liu-93385DiVA, id: diva2:624499
Merknad

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)||

Tilgjengelig fra: 2013-05-31 Laget: 2013-05-31 Sist oppdatert: 2018-08-24
Inngår i avhandling
1. Luminescent molecular recognition of pathognomonic and aging associated protein aggregates
Åpne denne publikasjonen i ny fane eller vindu >>Luminescent molecular recognition of pathognomonic and aging associated protein aggregates
2014 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Various protein inclusions have been recognized to be associated with aging and pathogenic conditions, such as in Alzheimer’s disease, Parkinson’s disease, Type 2 diabetes, and the prionoses Creutzfeldt-Jakob disease, Chronic wasting disease (CWD), and Mad cow disease. The causative transition of protein aggregation is the alteration in the conformation of the protein that renders the protein susceptible towards self-assembly. Variations in the physico-chemical ultrastructure of the protein deposit, i.e. the conformation and the chemical nature of the fibril constituent protein monomers, translate into specific structure-property phenotype, hence clinicopathology. Upon transmission and/or propagation this phenomenon gives rise to specific protein aggregate strains. Today most potential treatments of the protein conformational diseases have been a huge failure, effectively due to late diagnosis and subsequent therapeutic intervention. An imperative for efficient treatment is early detection and accurate identification for proper clinical diagnosis.

The purpose of the studies in this thesis was to develop highly sensitive methods for detection and discrimination of age- and disease associated protein deposits both for in vitro and ex vivo utilization.

Herein we have shown that, for in vitro usage, Nile red will bind to amyloid-like protein aggregates derived from a plethora of precursor proteins. It was also found that the fluorescence was insensitive to acidic assay conditions in contrast to the standard in vitro dye Thioflavin T (ThT). Further, Nile red was shown to discriminate between conformational isoforms thus enabling conformational typing of amyloid structures.

For the development of ex vivo detection methods we employed luminescent conjugated oligothiophenes (LCOs) and utilized the structure-conformation induced optical properties of this class of protein aggregate ligands. The heptameric oligothiophene h-FTAA was successfully used to detect, with high sensitivity, protein deposits from various systemic amyloidoses (ATTR, AA, AL-λ/κ, and the local amyloidosis AIAPP) derived from biopsy specimens. Also aging-associated protein deposits were detected which was found promising for early detection of potentially pathogenic protein inclusions. Further, LCO staining of tissue sections was found compatible with immunolabeling enabling subtyping of involved proteins. Early detection of amyloidosis also requires relatively non-invasive methods, why h-FTAA staining was directed towards fine-needle-aspirated (FNA) abdominal fat tissue smears. Staining of protein deposits and detection with high sensitivity was also found in the fat tissue smears.

In addition to the relatively rare prionoses it has lately been shown that Alzheimer’s, Parkinson’s diseases share similar properties as the prion pathologies. Hence the urgent need for ligands that will recognize specific disease specific strain aggregates. Using an established murine model for prion strain propagation we were able to discriminate two different prion strains, murine adapted Sheep Scrapie (mSS) and murine adapted Chronic wasting disease (mCWD) from each other by using multimodal fluorescence microscopy entailing emission/excitation spectral imaging and fluorescent lifetime imaging (FLIM).

In conclusion we have shown that the LCOs will recognize protein aggregates with high sensitivity and selectivity. In addition we have shown that the LCOs detect protein aggregates that Congo red failed to recognize thus allowing potentially early diagnosis. Last, we show that the LCOs will recognize and discriminate between different protein aggregate strains which potentially will allow disease specific therapeutic targeting.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2014. s. 77
Serie
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1596
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-106878 (URN)978-91-7519-334-2 (ISBN)
Disputas
2014-06-11, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 14:15 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2014-05-23 Laget: 2014-05-23 Sist oppdatert: 2018-04-25bibliografisk kontrollert
2. Multimodal Porphyrin-Based Conjugates: Synthesis and characterization for applications as amyloid ligands, photodynamic therapy agents and chiroptical materials
Åpne denne publikasjonen i ny fane eller vindu >>Multimodal Porphyrin-Based Conjugates: Synthesis and characterization for applications as amyloid ligands, photodynamic therapy agents and chiroptical materials
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Organic compounds that interact both with certain biological targets and display specific photophysical properties can be utilized as molecular tools to visualize and possibly effect disease related processes taking place in living organisms. In this regard, porphyrins are a class of naturally occurring molecules that possess intriguingly interesting photophysical properties where they can act as luminescent probes by emitting detectable light, as well as photosensitizers in the light mediated therapy called photodynamic therapy. In this thesis, the porphyrin structure has been synthetically combined with other molecule classes to achieve compounds with desirable multimodal characteristics.

Firstly, luminescent conjugated oligothiophenes (LCOs) that have extensively, and with great success, been utilized as fluorescent ligands for amyloid formations, have been conjugated to porphyrins to render oligothiophene porphyrin hybrids (OTPHs) comprising two optically active modalities. When applied as fluorescent amyloidophilic dyes for visualization of amyloid-β (Aβ), one of the pathological hallmarks in Alzheimer’s disease, an enhanced optical assignment of distinct aggregated forms of Aβ was afforded.  Thus, properly functionalized OTPHs could give us more information about pathological processes underlying devastating disorders, such as Alzheimer’s disease. In addition, the OTPHs can be associated with synthetic peptides inducing peptide folding into certain three-dimensional helical structures giving rise to novel optically active materials.

Secondly, this thesis also embraces porphyrins’ potential as photosensitizers in photodynamic therapy to kill cancer cells. Grounded on the prerequisites for an optimal photosensitizer, we designed porphyrin-based conjugates equipped with common carbohydrates for improved cancer cell selectivity and with a fluorinated glucose derivative, 2-fluoro 2-deoxy glucose, for advantageous metabolism in cancer cells. Furthermore, incorporation of a radioisotopic fluorine-18 atom into the glycoporphyrins could give the means for diagnostic use of the conjugates in positron emission tomography (PET).

In order to tether together the above-mentioned molecular moieties in a controlled fashion, we developed a robust synthetic strategy for asymmetrical functionalization of porphyrin core. The method involves chlorosulfonation of this otherwise inert tetrapyrrolic structure, followed by alkynylation. Parallelly to amide coupling reactions, copper(I)-catalyzed alkyne azide cycloaddition is used for fast and high-yielding late-stage conjugations. Overall, this thesis demonstrates how combining different molecular moieties in synthetic organic chemistry yields novel molecules with combined and improved multimodal properties for biological and medicinal applications, guided by the design-by-function methodology.      

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2018. s. 83
Serie
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1947
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-150522 (URN)10.3384/diss.diva-150522 (DOI)9789176852552 (ISBN)
Disputas
2018-11-09, Planck, Fysikhuset, Campus Valla, Linköping, 09:15 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2018-08-27 Laget: 2018-08-24 Sist oppdatert: 2019-09-26bibliografisk kontrollert

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