title: Pentameric thiophene-based ligands that spectrally discriminate amyloid-β and tau aggregates display distinct solvatochromism and viscosity-induced spectral shifts.
abstract: A wide range of neurodegenerative diseases are characterized by the deposition of multiple protein aggregates. Ligands for molecular characterization and discrimination of these pathological hallmarks are thus important for understanding their potential role in pathogenesis as well as for clinical diagnosis of the disease. In this regard, luminescent conjugated oligothiophenes (LCOs) have proven useful for spectral discrimination of amyloid-beta (Aβ) and tau neurofibrillary tangles (NFTs), two of the pathological hallmarks associated with Alzheimer's disease. Herein, the solvatochromism of a library of anionic pentameric thiophene-based ligands, as well as their ability to spectrally discriminate Aβ and tau aggregates, were investigated. Overall, the results from this study identified distinct solvatochromic and viscosity-dependent behavior of thiophene-based ligands that can be applied as indices to direct the chemical design of improved LCOs for spectral separation of Aβ and tau aggregates in brain tissue sections. The results also suggest that the observed spectral transitions of the ligands are due to their ability to conform by induced fit to specific microenvironments within the binding interface of each particular protein aggregate. We foresee that these findings might aid in the chemical design of thiophene-based ligands that are increasingly selective for distinct disease-associated protein aggregates.
authors.affiliation: Department of Chemistry, Linköping University, 581 83 Linköping (Sweden).
authors.forename: Rozalyn A
authors.initials: RA
authors.lastname: Simon
authors.forename: Hamid
authors.initials: H
authors.lastname: Shirani
authors.forename: K O Andreas
authors.initials: KO
authors.lastname: Aslund
authors.forename: Marcus
authors.initials: M
authors.lastname: Bäck
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.forename: Sam
authors.initials: S
authors.lastname: Gandy
authors.forename: K Peter R
authors.initials: KP
authors.lastname: Nilsson
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000032:analysis*; D001921:Brain / Q000473:pathology*; D006801:Humans; D008024:Ligands; D049408:Luminescent Agents / Q000737:chemistry; D061848:Optical Imaging; D066263:Protein Aggregation, Pathological / Q000175:diagnosis* / Q000473:pathology; D013876:Thiophenes / Q000737:chemistry; D014783:Viscosity; D016875:tau Proteins / Q000032:analysis*
chemical_list: D016229:Amyloid beta-Peptides; D008024:Ligands; D049408:Luminescent Agents; D013876:Thiophenes; D016875:tau Proteins
keywords: fluorescence; imaging agents; luminescent conjugated oligothiophenes; protein aggregates; solvatochromism
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