Novel Pentameric Thiophene Derivatives for in Vitro and in Vivo Optical Imaging of a Plethora of Protein Aggregates in Cerebral Amyloidoses
| Autor: | Adriano Aguzzi, Peter Konradsson, Mikael Lindgren, Tristan Bolmont, Mathias Jucker, Stefan Prokop, Patrick R. Hof, Eirik Glimsdal, Stefan A. Grathwohl, K. Peter R. Nilsson, Frank L. Heppner, Christina J. Sigurdson, David M. Holtzman, Therése Klingstedt, Per Hammarström, Andreas Åslund, Sam Gandy, Dara L. Dickstein |
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| Přispěvatelé: | University of Zurich |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
1303 Biochemistry
Protein aggregation Acetates 01 natural sciences Biochemistry chemistry.chemical_compound Mice Alzheimers-Disease 0303 health sciences Brain Diseases Molecular Structure Chemistry Brain Neurodegenerative Diseases General Medicine Amyloidosis Beta-peptide Beta-Peptide 3. Good health Molecular Medicine Molecular probe Amyloid Conformational States 10208 Institute of Neuropathology Mice Transgenic 610 Medicine & health Thiophenes Thioflavin-T 010402 general chemistry Fibril Article Transgenic Mice 03 medical and health sciences Microscopy Electron Transmission In vivo Animals Humans 030304 developmental biology Amyloid beta-Peptides Conjugated Polyelectrolytes In vitro 0104 chemical sciences Disease Models Animal 1313 Molecular Medicine Oligomers 570 Life sciences biology Fibrils Probes Ex vivo |
| Zdroj: | ACS Chemical Biology; Vol 4 |
| ISSN: | 1554-8937 |
| DOI: | 10.1021/cb900112v |
| Popis: | 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, showed conformation-dependent optical properties and could be utilized for ex vivo spectral assignment of distinct prion deposits from two mouse-adapted prion strains. p-FTAA also revealed staining of transient soluble pre-fibrillar non-thioflavinophilic Aβ- assemblies during in vitro fibrillation of Aβ peptides. In brain tissue samples, Aβ deposits and neurofibrillary tangles (NFTs) were readily identified by a strong fluorescence from p-FTAA and the LCO staining showed complete co-localization with conventional antibodies (6E10 and AT8), indicating that p-FTAA detects all the immuno-positive aggregated proteinaceous species in Alzheimer disease, but with significantly shorter imaging time (100 fold) compared to immunofluorescence. In addition, a patchy islet-like staining of individual Aβ plaque was unveiled by the anti-oligomer A11 antibody during co-staining with p-FTAA, suggesting that pre-fibrillar species are likely an intrinsic component of Aβ plaques in human brain. The major hallmarks of Alzheimer’s disease, namely Aβ aggregates versus NFTs could also be distinguished due to 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, Aβ−tau interactions and pathogenesis both ex vivo and in vivo. |
| Databáze: | OpenAIRE |
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