RESUMEN
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 (Aß) 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 Aß 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 Aß 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.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/análisis , Encéfalo/patología , Sustancias Luminiscentes , Agregación Patológica de Proteínas/diagnóstico , Tiofenos , Proteínas tau/análisis , Enfermedad de Alzheimer/patología , Humanos , Ligandos , Sustancias Luminiscentes/química , Imagen Óptica , Agregación Patológica de Proteínas/patología , Tiofenos/química , ViscosidadRESUMEN
Protein misfolding diseases are characterized by deposition of protein aggregates, and optical ligands for molecular characterization of these disease-associated structures are important for understanding their potential role in the pathogenesis of the disease. Luminescent conjugated oligothiophenes (LCOs) have proven useful for optical identification of a broader subset of disease-associated protein aggregates than conventional ligands, such as thioflavinâ T and Congo red. Herein, the molecular requirements for achieving LCOs able to detect nonthioflavinophilic Aß aggregates or non-congophilic prion aggregates, as well as spectrally discriminate Aß and tau aggregates, were investigated. An anionic pentameric LCO was subjected to chemical engineering by: 1)â replacing thiophene units with selenophene or phenylene moieties, or 2)â alternating the anionic substituents along the thiophene backbone. In addition, two asymmetric tetrameric ligands were generated. Overall, the results from this study identified conformational freedom and extended conjugation of the conjugated backbone as crucial determinants for obtaining superior thiophene-based optical ligands for sensitive detection and spectral assignment of disease-associated protein aggregates.
Asunto(s)
Amiloide/química , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Proteínas/química , Tiofenos/química , Tiofenos/síntesis química , Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Animales , Encéfalo/patología , Ratones , Ratones Transgénicos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Fluorescent probes identifying protein aggregates are of great interest, as deposition of aggregated proteins is associated with many devastating diseases. Here, we report that a fluorescent amyloid ligand composed of two distinct molecular moieties, an amyloidophilic pentameric oligothiophene and a porphyrin, can be utilized for spectral and lifetime imaging assessment of recombinant Aß 1-42 amyloid fibrils and Aß deposits in brain tissue sections from a transgenic mouse model with Alzheimer's disease pathology. The enhanced spectral range and distinct lifetime diversity of this novel oligothiophene-porphyrin-based ligand allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye.
Asunto(s)
Péptidos beta-Amiloides/química , Colorantes Fluorescentes/química , Fragmentos de Péptidos/química , Porfirinas/química , Tiofenos/química , Péptidos beta-Amiloides/metabolismo , Animales , Modelos Animales de Enfermedad , Colorantes Fluorescentes/metabolismo , Ligandos , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/metabolismo , Multimerización de ProteínaRESUMEN
The Environmental Specimen Bank (ESB) at the Swedish Museum of Natural History, Stockholm, constitutes a base for ecotoxicological research as well as for spatial and trend monitoring of contaminants in Swedish fauna. Since the 1960s, tissue samples from more than 150000 organisms have been collected from different groups of animals, habitats and types of landscape. Samples from the ESB have been utilized for retrospective studies of trace elements, organohalogenated compounds and radionuclides. Among many matrices utilized, eggs of guillemot (Uria aalge) have proven to be an appropriate matrix for assessment of the contamination of the Baltic Sea. Results from time trend studies based on this material showing trends in concentrations of DDT, PCB, PCDD/F, and mercury are presented in this paper.