The amino terminus of tau inhibits kinesin-dependent axonal transport: Implications for filament toxicity

Nichole E. LaPointe, Gerardo Morfini, Gustavo Pigino, Irina N. Gaisina, Alan P. Kozikowski, Lester I. Binder, Scott T. Brady

Research output: Contribution to journalArticlepeer-review

Abstract

The neuropathology of Alzheimer's disease (AD) and other tauopathies is characterized by filamentous deposits of the microtubule-associated protein tau, but the relationship between tau polymerization and neurotoxicity is unknown. Here, we examined effects of filamentous tau on fast axonal transport (FAT) using isolated squid axoplasm. Monomeric and filamentous forms of recombinant human tau were perfused in axoplasm, and their effects on kinesin- and dyneindependent FAT rates were evaluated by video microscopy. Although perfusion of monomeric tau at physiological concentrations showed no effect, tau filaments at the same concentrations selectively inhibited anterograde (kinesin-dependent) FAT, triggering the release of conventional kinesin from axoplasmic vesicles. Pharmacological experiments indicated that the effect of tau filaments on FAT is mediated by protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK-3) activities. Moreover, deletion analysis suggested that these effects depend on a conserved 18-amino-acid sequence at the amino terminus of tau. Interestingly, monomeric tau isoforms lacking the C-terminal half of the molecule (including the microtubule binding region) recapitulated the effects of full-length filamentous tau. Our results suggest that pathological tau aggregation contributes to neurodegeneration by altering a regulatory pathway for FAT.

Original languageEnglish (US)
Pages (from-to)440-451
Number of pages12
JournalJournal of neuroscience research
Volume87
Issue number2
DOIs
StatePublished - Feb 1 2009

Keywords

  • Alzheimer's disease
  • Axonal transport
  • GSK3
  • Kinesin
  • PP1
  • Tau
  • Tau filament

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'The amino terminus of tau inhibits kinesin-dependent axonal transport: Implications for filament toxicity'. Together they form a unique fingerprint.

Cite this