title: Ligand-dependent tau filament formation: implications for Alzheimer's disease progression.
abstract: The mechanism through which arachidonic acid induces the polymerization of tau protein into filaments under reducing conditions was characterized through a combination of fluorescence spectroscopy and electron microscopy. Results show that polymerization follows a ligand-mediated mechanism, where binding of arachidonic acid is an obligate step preceding tau-tau interaction. Homopolymerization begins with rapid (on the order of seconds) nucleation, followed by a slower elongation phase (on the order of hours). Although essentially all synthetic filaments have straight morphology at early time points, they interact with thioflavin-S and monoclonal antibody Alz50 much like authentic paired helical filaments, suggesting that the conformation of tau protein is similar in the two filament forms. Over a period of days, synthetic straight filaments gradually adopt paired helical morphology. These results define a novel pathway of tau filament formation under reducing conditions, where oxidation may contribute to final paired helical morphology, but is not a necessary prerequisite for efficient nucleation or elongation of tau filaments.
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: King
authors.forename: V
authors.initials: V
authors.lastname: Ahuja
authors.forename: L I
authors.initials: LI
authors.lastname: Binder
authors.forename: J
authors.initials: J
authors.lastname: Kuret
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D018450:Disease Progression; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008959:Models, Neurological; D016874:Neurofibrillary Tangles / Q000648:ultrastructure*; D010084:Oxidation-Reduction; D011108:Polymers / Q000378:metabolism; D013696:Temperature; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D008024:Ligands; D011108:Polymers; D016875:tau Proteins