Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses

Andreas Åslund, Christina J. Sigurdson, Therése Klingstedt, Stefan Grathwohl, Tristan Bolmont, Dara L. Dickstein, Eirik Glimsdal, Stefan Prokop, Mikael Lindgren, Peter Konradsson, David M. Holtzman, Patrick R. Hof, Frank L. Heppner, Samuel Gandy, Mathias Jucker, Adriano Aguzzi, Per Hammarström, K. Peter R. Nilsson

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188 Scopus citations

Abstract

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 staining of transient soluble pre-fibrillar non-thioflavinophilic Aβ-assemblies during in vitro fi-brillation 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). 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. The major hallmarks of Alzheimer's disease, namely, Aβ 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, Aβ-tau interactions, and pathogenesis both ex vivo and in vivo.

Original languageEnglish
Pages (from-to)673-684
Number of pages12
JournalACS Chemical Biology
Volume4
Issue number8
DOIs
StatePublished - Aug 21 2009

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    Åslund, A., Sigurdson, C. J., Klingstedt, T., Grathwohl, S., Bolmont, T., Dickstein, D. L., Glimsdal, E., Prokop, S., Lindgren, M., Konradsson, P., Holtzman, D. M., Hof, P. R., Heppner, F. L., Gandy, S., Jucker, M., Aguzzi, A., Hammarström, P., & Nilsson, K. P. R. (2009). Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses. ACS Chemical Biology, 4(8), 673-684. https://doi.org/10.1021/cb900112v