Journal
MOLECULAR AND CELLULAR NEUROSCIENCE
Volume 39, Issue 3, Pages 302-313Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mcn.2008.07.010
Keywords
Gene transfer; Neuroprotection; Oxidative stress; Transgenic; Knock-out
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Funding
- Finland's Academy
- Sigrid Juselius Foundation
- Institute for the study of Aging
- Nordic Centre of Excellence Program in Molecular Medicine
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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 (A beta). Nrf2-ARE pathway was attenuated in APP/PS1 transgenic mouse brain at the time of A beta deposition. Boosting the activity of the Nrf2-ARE pathway by tert-butylhydroquinone treatment or adenoviral Nrf2 gene transfer protected against A beta 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. (C) 2008 Elsevier Inc. All rights reserved.
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