The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer's disease
Open accessAbstract
The amyloid hypothesis of Alzheimer's disease (AD) postulates that amyloid-β (Aβ) 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 Aβ toward an insoluble Aβ pool without concomitant change in total brain Aβ 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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Cites
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“Nrf2 has a relatively rapid turnover (half-life 20 min), and its activity is regulated by the repressor protein Keap1, which targets Nrf2 for proteosomal degradation (21, 22).”
BackgroundNSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo
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A genomic screen for activators of the antioxidant response element
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Cited by
The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis
Yamamoto, M., Kensler, T. W., & Motohashi, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00023.2017 · Cited by 1,968
Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory
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When NRF2 Talks, Who's Listening?
Wakabayashi, N., Slocum, S. L., Skoko, J. J., Shin, S., & Kensler, T. W. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3216 · Cited by 595
Nrf2/Keap1/ARE signaling: Towards specific regulation
Ulasov, A. V., Rosenkranz, A. A., Georgiev, G. P., & Sobolev, A. S. (2022) · Life Sciences · doi:10.1016/j.lfs.2021.120111 · Cited by 508
Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases
(2018) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2018.05.006 · Cited by 455
Metadata
- Authors
- Kanninen, K., Heikkinen, R., Malm, T., Rolova, T., Kuhmonen, S., Leinonen, H., Ylä-Herttuala, S., Tanila, H., Levonen, A.-L., Koistinaho, M., & Koistinaho, J.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2009-09-22
- Volume
- 106
- Issue
- 38
- Pages
- 16505-16510
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2019172653
- Cited by
- 293
- References
- 11
- FWCI
- 7.68
- Type
- journal article
- Language
- en
- Open access
- green
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- Kanninen, K., Heikkinen, R., Malm, T., Rolova, T., Kuhmonen, S., Leinonen, H., Ylä-Herttuala, S., Tanila, H., Levonen, A.-L., Koistinaho, M., & Koistinaho, J. (2009). Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0908397106
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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