Imaging Distinct Conformational States of Amyloid-β Fibrils in Alzheimer’s Disease Using Novel Luminescent Probes

Nilsson, K. Peter R.; Åslund, Andreas; Berg, Ina; Nyström, Sofie; Konradsson, Peter; Herland, Anna; Inganäs, Olle; Stabo-Eeg, Frantz; Lindgren, Mikael; Westermark, Gunilla T.; Lannfelt, Lars; Nilsson, Lars; Hammarström, Per

doi:10.1021/cb700116u

Cited by 173 publications

(208 citation statements)

References 27 publications

(36 reference statements)

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“…Instead of simply measuring the total amount of aggregated protein, heterogeneous populations of specific protein aggregates can be differentiated by LCP staining. This phenomenon was recently observed in a transgenic mouse model with AD pathology, where a striking heterogeneity in the characteristic plaques composed of the beta-amyloid peptide ͑A␤͒ was identified with the LCPs (Nilsson et al, 2007). LCP staining of brain tissue slices revealed different subpopulations of plaques, seen as plaques with different colors.…”

Section: Strains and Small Molecule Dyessupporting

confidence: 53%

Chemical and biophysical insights into the propagation of prion strains

Falsig¹,

Nilsson

Knowles

et al. 2008

HFSP Journal

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Section: Strains and Small Molecule Dyessupporting

confidence: 53%

Chemical and biophysical insights into the propagation of prion strains

Falsig¹,

Nilsson

Knowles

et al. 2008

HFSP Journal

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“…Before exposure, when the level of peptide aggregation was high, the fluorescence intensity was greater than double that following photo-induced disassociation. Apart from the absence of blue shift in the excitation spectrum, the spectra appear consistent with those measured for PTAA in the presence and absence of Aβ peptide aggregation, as investigated previously 55 .…”

Section: Resultssupporting

confidence: 88%

“…5b, lie almost directly on top of each other, demonstrating that the disassociation kinetics are highly repeatable. Reaggregation curves were also collected in the same manner, normalized and aligned such that time zero was when the UV light was turned off, shown in luminescent conjugated polyelectrolyte probes (LCPs), which were specifically developed as markers for amyloid fibrils 55,57 . These dyes bind non-covalently with fibrils and have spectra that do not overlap with that of the photo-linker.…”

Section: Resultsmentioning

confidence: 99%

Photocontrol of Reversible Amyloid Formation with a Minimal-Design Peptide

et al. 2012

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Amyloid aggregates are highly ordered fibrillar assemblies of polypeptides involved in a number of neurodegenerative diseases. Very little is known on the pathways of self-assembly of peptides into the final amyloid fibrils, which is due in part to the difficulty of triggering the aggregation process in a controlled manner. Here we present the design and validation of a cross-linked hexapeptide that reversibly aggregates and dissociates under ultraviolet light irradiation control. First molecular dynamics simulations were carried out to identify, among hundreds of possible sequences, those with the highest propensity to form ordered (-sheet) oligomers in the trans state of the azobenzene cross-linker, and at the same time with the highest solubility in the cis state. In the simulations, the peptides were observed to spontaneously form ordered oligomers with cross-contacts when the cross-linker was in the trans state, whereas in the cis state they self-assemble into amorphous aggregates. For the most promising sequence emerging from the simulations (Ac-Cys-His-Gly-Gln-Cys-Lys-NH2 cross-linked at the two cysteine residues), the photoisomerization of the azobenzene group was shown to induce reversible aggregation by time-resolved light scattering and fluorescence measurements. The amyloid-like fibrillar topology was confirmed by electron microscopy. Potential applications of minimally designed peptides with photoswitchable amyloidogenic propensity are briefly discussed. AbstractAmyloid aggregates are highly ordered fibrillar assemblies of polypeptides involved in a number of neurodegenerative diseases. Very little is known on the pathways of self-assembly of peptides into the final amyloid fibrils, which is due in part to the difficulty of triggering the aggregation process in a controlled manner. Here we present the design and validation of a cross-linked hexapeptide that reversibly aggregates and dissociates under ultraviolet light irradiation control. First molecular dynamics simulations were carried out to identify, among hundreds of possible sequences, those with the highest propensity to form ordered (β-sheet) oligomers in the trans state of the azobenzene cross-linker, and at the same time with the highest solubility in the cis state. In the simulations, the peptides were observed to spontaneously form ordered oligomers with cross-β contacts when the cross-linker was in the trans state, whereas in the cis state they self-assemble into amorphous aggregates. For the most promising sequence emerging from the simulations (Ac-Cys-His-Gly-GlnCys-Lys-NH 2 cross-linked at the two cysteine residues), the photo-isomerization of the azobenzene group was shown to induce reversible aggregation by time-resolved light scattering and fluorescence measurements. The amyloid-like fibrillar topology was confirmed by electron microscopy. Potential applications of minimally-designed peptides with photoswitchable amyloidogenic propensity are briefly discussed.

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“…LCPs have now demonstrated the ability to monitor fibril formation in vitro and by persistent research, the probes were also evaluated as conformation-sensitive optical tools in imaging of more complex systems as tissue samples [39], [75]. The results showed that the LCPs are excellent tools in discriminating amyloid, even in tissue.…”

Section: Lcps As Fluorescent Reporters For Protein Aggregates and Cellsmentioning

confidence: 99%

Poly-and oligothiophenes : Optical probes for multimodal fluorescent assessment of biological processes

Magnusson¹

2015

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IICover: Fibroblasts and melanoma cells stained with a fluorescent thiophene probe called p-HTIm, DAPI and antibodies against ER, proteasomes, α-tubulin, fibronectin, or mitotracker against mitochondria.During the course of the research underlying this thesis, Karin Magnusson was enrolled in Forum Scientium, a multidisciplinary doctoral program at Linköping University, Sweden. ABSTRACTOne interesting class of molecules in the research field of imaging biological processes is luminescent conjugated polythiophenes, LCPs. These fluorescent probes have a flexible backbone consisting of repetitive thiophene units. Due to this backbone, the probes possess unique abilities to give rise to different spectral signatures depending on their target and environment. LCPs are a polydispersed material meaning there is an uneven distribution of lengths of the probe. Recently, monodispersed chemically well-defined material denoted luminescent conjugated oligothiophenes, LCOs, with an exact number of repetitive units and distinct sidechain functionalities along the backbone has been developed. LCOs have the advantages of being smaller which leads to higher ability to cross the blood brain barrier. The synthesis of minor chemical alterations is also more simplified due to the well-defined materials. During my doctoral studies I have used both LCPs and LCOs to study biological processes such as conformational variation of protein aggregates in prion diseases and cellular uptake in normal cells and cancer cells. The research has generally been based on the probes capability to emit light upon irradiation and the interaction with their targets has mainly been assessed through variations in fluorescence intensity, emission-and excitation profiles and fluorescence lifetime decay. These studies verified the utility of LCPs and LCOs for staining and discrimination of both prion strains and cell phenotypes. The results also demonstrated the pronounced influence minor chemical modifications have on the LCO´s staining capacity. IV POPULÄRVETENSKAPLIG SAMMANFATTNING LYSANDE MOLEKYLER FÖR STUDIER AV BIOLOGISKA PROCESSERLuminiscenta konjugerade polytiofener, LCPs, är en väldigt intressant typ av molekyl som kan användas för att studera processer i biologiska system. Strukturen hos dessa fluorescerande molekyler kan liknas vid olika element som är fästa vid en ryggrad. De olika elementen ger molekylen dess affinitet för sin målmolekyl, medan ryggraden är mest ansvarig för molekylens optiska egenskaper. Ryggraden ändrar sin struktur beroende på målmolekylen och resultatet kan avläsas med ett flertal fluorescens-metoder. Längden på ryggraden hos LCPs varierar och varje parti av en LCP består därmed av en blandning längder och storlekar. De senaste åren har Peter Nilssons forskargrupp utvecklat LCPs till molekyler med väldefinierad längd på ryggraden som då betecknas luminiscenta konjugerade oligotiofener, LCOs. Dessa mindre molekyler har större möjlighet att passera blodhjärnbarriären samt att syntesen för små kemiska modifieringar av elementen ...

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Imaging Distinct Conformational States of Amyloid-β Fibrils in Alzheimer’s Disease Using Novel Luminescent Probes

Cited by 173 publications

References 27 publications

Chemical and biophysical insights into the propagation of prion strains

Chemical and biophysical insights into the propagation of prion strains

Photocontrol of Reversible Amyloid Formation with a Minimal-Design Peptide

Poly-and oligothiophenes : Optical probes for multimodal fluorescent assessment of biological processes

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