title: Modulation and detection of tau aggregation with small-molecule ligands.
abstract: Recent results from high-throughput and other screening approaches reveal that small molecules can directly interact with recombinant full-length tau monomers and fibrillar tau aggregates in three distinct modes. First, in the high concentration regime (>10 micromolar), certain anionic molecules such as Congo red efficiently promote tau filament formation through a nucleation-elongation mechanism involving a dimeric nucleus and monomer-mediated elongation. These compounds are useful for modeling tau aggregation in vitro and in biological models. Second, in the low concentration regime (<1 micromolar), other ligands, including cyanine dyes, display aggregation antagonist activity. Compounds that can prevent or reverse fibrillization are candidate modifiers of disease pathology. Finally, certain compounds bind mature tau fibrils with varying affinities at multiple binding sites without modulating the aggregation reaction. For some ligands, >10-fold selectivity for tau aggregates relative to filaments composed of beta-amyloid or alpha-synuclein can be demonstrated at the level of binding affinity. Together these observations suggest that small-molecules have utility for interrogating the tau aggregation pathway, for inhibiting neuritic lesion formation, and for selective pre-mortem detection of neurofibrillary lesions through whole brain imaging.
authors.affiliation: Center for Molecular Neurobiology, Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Chang
authors.forename: Nicolette S
authors.initials: NS
authors.lastname: Honson
authors.forename: Bhaswati
authors.initials: B
authors.lastname: Bandyopadhyay
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Funk
authors.forename: Jordan R
authors.initials: JR
authors.lastname: Jensen
authors.forename: Sohee
authors.initials: S
authors.lastname: Kim
authors.forename: Swati
authors.initials: S
authors.lastname: Naphade
authors.forename: Jeff
authors.initials: J
authors.lastname: Kuret
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D006801:Humans; D008751:Methylene Blue / Q000627:therapeutic use; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D008751:Methylene Blue