The generation of a 17 kDa neurotoxic fragment: An alternative mechanism by which tau mediates β-amyloid-induced neurodegeneration

So Young Park, Adriana Ferreira*

*Corresponding author for this work

Research output: Contribution to journalArticle

215 Scopus citations

Abstract

Recently, we have shown that the microtubule-associated protein tau is essential for β-amyloid (Aβ)-induced neurotoxicity in hippocampal neurons. However, the mechanisms by which tau mediates Aβ-induced neurite degeneration remain poorly understood. In the present study, we analyzed whether tau cleavage played a role in these events. Our results showed that pre-aggregated Aβ induced the generation of a 17 kDa tau fragment in cultured hippocampal neurons. The generation of this fragment was preceded by the activation of calpain-1. Conversely, inhibitors of this protease, but not of caspases, completely prevented tau proteolysis leading to the generation of the 17 kDa fragment and significantly reduced Aβ-induced neuronal death. Furthermore, the expression of this fragment in cultured hippocampal neurons induced the formation of numerous varicosity-bearing tortuous processes, as well as the complete degeneration of some of those neurite processes. These results suggest that Aβ-induced neurotoxicity may be mediated, at least in part, through the calpain-mediated generation of a toxic 17 kDa tau fragment. Collectively, these results provide insight into a novel mechanism by which tau could mediate Aβ-induced neurotoxicity.

Original languageEnglish (US)
Pages (from-to)5365-5375
Number of pages11
JournalJournal of Neuroscience
Volume25
Issue number22
DOIs
StatePublished - Jun 1 2005

Keywords

  • Alzheimer
  • Amyloid
  • Apoptosis
  • Degeneration
  • Hippocampus
  • Neurotoxicity
  • Proteolysis

ASJC Scopus subject areas

  • Neuroscience(all)

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