Nuclear factor erythroid 2-related factor 2 protects against beta amyloid

Katja Kanninen, Tarja M. Malm, Henna Kaisa Jyrkkänen, Gundars Goldsteins, Velta Keksa-Goldsteine, Heikki Tanila, Masayuki Yamamoto, Seppo Ylä-Herttuala, Anna Liisa Levonen, Jari Koistinaho

Research output: Contribution to journalArticlepeer-review

171 Citations (Scopus)

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates the up-regulation of cytoprotective genes via the antioxidant response element (ARE). In the pathogenesis of Alzheimer's disease (AD) current evidence supports the role of oxidative stress. Considering the protective role of Nrf2 against oxidative injury, we studied Nrf2 and Nrf2-ARE target genes in transgenic AD mice and tested whether Nrf2 could confer neuroprotection against amyloid-beta peptides (Aβ). Nrf2-ARE pathway was attenuated in APP/PS1 transgenic mouse brain at the time of Aβ deposition. Boosting the activity of the Nrf2-ARE pathway by tert-butylhydroquinone treatment or adenoviral Nrf2 gene transfer protected against Aβ toxicity. This neuroprotection was associated with increased expression of Nrf2 target genes and reduced phosphorylation of p66Shc, a marker of increased susceptibility for oxidative stress. The findings suggest that the Nrf2-ARE pathway may be impaired in AD and that induction of the Nrf2-ARE defence mechanism may prevent or delay AD-like pathology.

Original languageEnglish
Pages (from-to)302-313
Number of pages12
JournalMolecular and Cellular Neuroscience
Volume39
Issue number3
DOIs
Publication statusPublished - 2008 Oct 29

Keywords

  • Gene transfer
  • Knock-out
  • Neuroprotection
  • Oxidative stress
  • Transgenic

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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