title: Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses.
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 Abeta-assemblies during in vitro fibrillation of Abeta peptides. In brain tissue samples, Abeta 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 Abeta plaque was unveiled by the anti-oligomer A11 antibody during co-staining with p-FTAA. The major hallmarks of Alzheimer's disease, namely, Abeta 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, Abeta-tau interactions, and pathogenesis both ex vivo and in vivo.
authors.affiliation: Department of Chemistry, IFM, Linköping University, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Aslund
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Sigurdson
authors.forename: Therése
authors.initials: T
authors.lastname: Klingstedt
authors.forename: Stefan
authors.initials: S
authors.lastname: Grathwohl
authors.forename: Tristan
authors.initials: T
authors.lastname: Bolmont
authors.forename: Dara L
authors.initials: DL
authors.lastname: Dickstein
authors.forename: Eirik
authors.initials: E
authors.lastname: Glimsdal
authors.forename: Stefan
authors.initials: S
authors.lastname: Prokop
authors.forename: Mikael
authors.initials: M
authors.lastname: Lindgren
authors.forename: Peter
authors.initials: P
authors.lastname: Konradsson
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hof
authors.forename: Frank L
authors.initials: FL
authors.lastname: Heppner
authors.forename: Samuel
authors.initials: S
authors.lastname: Gandy
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
authors.forename: Per
authors.initials: P
authors.lastname: Hammarström
authors.forename: K Peter R
authors.initials: KP
authors.lastname: Nilsson
mesh_terms: D000085:Acetates / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000378:metabolism / Q000648:ultrastructure; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001927:Brain Diseases / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D013876:Thiophenes / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000085:Acetates; D016229:Amyloid beta-Peptides; D013876:Thiophenes; C572917:pentamer formyl thiophene acetic acid