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Novel Pentameric Thiophene Derivatives for in Vitro and in Vivo Optical Imaging of a Plethora of Protein Aggregates in Cerebral Amyloidoses

Åslund, Andreas (author)
Linköpings universitet,Organisk Kemi,Tekniska högskolan
Sigurdson, Christina J (author)
Institute of Neuropathology, Department of Pathology, Universitätsspital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland
Klingstedt, Therése (author)
Linköpings universitet,Kemi,Tekniska fakulteten
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Grathwohl, Stefan (author)
Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, D-72076 Tuebingen, Germany
Bolmont, Tristan (author)
Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, D-72076 Tuebingen, Germany
Dickstein, Dara L (author)
Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA
Glimsdal, Eirik (author)
Department of Physics, Norwegian University of Science and Technology, N-7491 Trondheim, Norway
Prokop, Stefan (author)
Department of Neuropathology, Charité-Universitätsmedizin Berlin, D-13353 Berlin, Germany
Lindgren, Mikael (author)
Department of Physics, Norwegian University of Science and Technology, N-7491 Trondheim, Norway
Konradsson, Peter (author)
Linköpings universitet,Organisk Kemi,Tekniska högskolan
Holtzman, David M (author)
Department of Neurology, Alzheimer’s Disease Research Center, Washington University, St. Louis, Missouri 63110, USA
Hof, Patrick R (author)
Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA
Heppner, Frank L (author)
Department of Neuropathology, Charité-Universitätsmedizin Berlin, D-13353 Berlin, Germany
Gandy, Samuel (author)
Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York, New York 10029, USA
Jucker, Mathias (author)
Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, D-72076 Tuebingen, Germany
Aguzzi, Adriano (author)
Institute of Neuropathology, Department of Pathology, Universitätsspital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland
Hammarström, Per (author)
Linköpings universitet,Biokemi,Tekniska högskolan
Nilsson, Peter (author)
Linköpings universitet,Organisk Kemi,Tekniska högskolan
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 (creator_code:org_t)
2009-07-30
2009
English.
In: ACS CHEMICAL BIOLOGY. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 4:8, s. 673-684
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  • Journal article (peer-reviewed)
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  • 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.

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NATURAL SCIENCES
NATURVETENSKAP

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