title: Evidence for independent mechanisms and a multiple-hit model of tau assembly.
abstract: Formation of inclusions containing polymerized tau protein is a hallmark of Alzheimer's disease and related disorders. In vitro studies have demonstrated the ability of polyglycosaminoglycans and fatty acids to promote tau polymerization. In this report, we examined their impact on tau polymerization separately and together. Tau assembly with only arachidonic acid was faster than that with only heparin. The presence of dithiothreitol reduced heparin-promoted tau assembly while enhancing arachidonic acid reactions. However, simultaneous use of these molecules increased the rate of filament assembly substantially, negated the effects of the reducing agent, and has very little effect on the morphology of filaments. The increases in polymerization resulted from accelerated nucleation. Finally, a FTDP-17 mutation was identified that could complement heparin to generate assembly kinetics similar to that of wild-type tau with both inducers. Our results support a multiple-hit model where several induced changes in tau can function independently to promote tau assembly.
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: DeTure
authors.forename: Brian
authors.initials: B
authors.lastname: Granger
authors.forename: Andrew
authors.initials: A
authors.lastname: Grover
authors.forename: Mike
authors.initials: M
authors.lastname: Hutton
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Yen
mesh_terms: D001665:Binding Sites; D003460:Crystallization / Q000379:methods; D019281:Dimerization; D008956:Models, Chemical; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000648:ultrastructure; D011485:Protein Binding; D011487:Protein Conformation; D016875:tau Proteins / Q000737:chemistry* / Q000648:ultrastructure*
chemical_list: D046912:Multiprotein Complexes; D016875:tau Proteins