title: Distinct Spacing Between Anionic Groups: An Essential Chemical Determinant for Achieving Thiophene-Based Ligands to Distinguish β-Amyloid or Tau Polymorphic Aggregates.
abstract: The accumulation of protein aggregates is associated with many devastating neurodegenerative diseases and the existence of distinct aggregated morphotypes has been suggested to explain the heterogeneous phenotype reported for these diseases. Thus, the development of molecular probes able to distinguish such morphotypes is essential. We report an anionic tetrameric oligothiophene compound that can be utilized for spectral assignment of different morphotypes of β-amyloid or tau aggregates present in transgenic mice at distinct ages. The ability of the ligand to spectrally distinguish between the aggregated morphotypes was reduced when the spacing between the anionic substituents along the conjugated thiophene backbone was altered, which verified that specific molecular interactions between the ligand and the protein aggregate are necessary to detect aggregate polymorphism. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between different morphotypes of protein aggregates.
authors.affiliation: Department of Chemistry, Linköping University, SE-581 83 Linköping (Sweden).
authors.forename: Therése
authors.initials: T
authors.lastname: Klingstedt
authors.affiliation: Department of Chemistry, Linköping University, SE-581 83 Linköping (Sweden).
authors.forename: Hamid
authors.initials: H
authors.lastname: Shirani
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen (Germany).|DZNE, German Center for Neurodegenerative Diseases, Tübingen (Germany).
authors.forename: Jasmin
authors.initials: J
authors.lastname: Mahler
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen (Germany).|DZNE, German Center for Neurodegenerative Diseases, Tübingen (Germany).
authors.forename: Bettina M
authors.initials: BM
authors.lastname: Wegenast-Braun
authors.affiliation: Department of Chemistry, Linköping University, SE-581 83 Linköping (Sweden).
authors.forename: Sofie
authors.initials: S
authors.lastname: Nyström
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge (United Kingdom).
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen (Germany).|DZNE, German Center for Neurodegenerative Diseases, Tübingen (Germany).
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
authors.affiliation: Department of Chemistry, Linköping University, SE-581 83 Linköping (Sweden). petni@ifm.liu.se.
authors.forename: K Peter R
authors.initials: KP
authors.lastname: Nilsson
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D000838:Anions / Q000737:chemistry*; D001921:Brain / Q000473:pathology; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D008024:Ligands; D049408:Luminescent Agents / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D015335:Molecular Probes; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology; D011506:Proteins / Q000737:chemistry*; D013876:Thiophenes / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D000838:Anions; D005456:Fluorescent Dyes; D008024:Ligands; D049408:Luminescent Agents; D015335:Molecular Probes; D011506:Proteins; D013876:Thiophenes
keywords: Alzheimer’s disease; aggregates; fluorescence; luminescent conjugated oligothiophenes; proteins