• Katja Kanninen, Riikka Heikkinen, Tarja Malm, Taisia Rolova, Susanna Kuhmonen, Hanna Leinonen, Seppo Ylä-Herttuala, Heikki Tanila, Anna-Liisa Levonen, Milla Koistinaho, and Jari Koistinaho.
• Departments of Neurobiology and Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FI-70211 Kuopio, Finland.
• Proc. Natl. Acad. Sci. U.S.A. 2009 Sep 22;106(38):16505-10.

AbstractThe amyloid hypothesis of Alzheimer's disease (AD) postulates that amyloid-beta (Abeta) deposition and neurotoxicity play a causative role in AD; oxidative injury is thought to be central in the pathogenesis. An endogenous defense system against oxidative stress is induced by binding of the transcription factor nuclear factor E2-related factor 2 (Nrf2) to the antioxidant response element (ARE) enhancer sequence. The Nrf2-ARE pathway is activated in response to reactive oxygen species to trigger the simultaneous expression of numerous protective enzymes and scavengers. To exploit the Nrf2-ARE pathway therapeutically, we delivered Nrf2 bilaterally into the hippocampus of 9-month-old transgenic AD mice (APP/PS1 mice) using a lentiviral vector encoding human Nrf2. The data indicate that significant reductions in spatial learning deficits of aged APP/PS1 mice in a Morris Water Maze can be achieved by modulating levels of Nrf2 in the brain. Memory improvement in APP/PS1 mice after Nrf2 transduction shifts the balance between soluble and insoluble Abeta toward an insoluble Abeta pool without concomitant change in total brain Abeta burden. Nrf2 gene transfer is associated with a robust reduction in astrocytic but not microglial activation and induction of Nrf2 target gene heme oxygenase 1, indicating overall activation of the Nrf2-ARE pathway in hippocampal neurons 6 months after injection. Results warrant further exploration of the Nrf2-ARE pathway for treatment of AD and suggest that the Nrf2-ARE pathway may represent a potential therapeutic strategy to pursue in AD in humans, particularly in view of the multiple mechanisms by which Nrf2 can exert its protective effects.

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