Evidence for independent mechanisms and a multiple-hit model of tau assembly

Michael DeTure, Brian Granger, Andrew Grover, Mike Hutton, Shu Hui Yen

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)858-864
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume339
Issue number3
DOIs
StatePublished - Jan 20 2006

Keywords

  • Filament assembly
  • Tau proteins
  • Tauopathies

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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