NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer’s models
Open accessAbstract
Significance Considering that Alzheimer’s disease (AD) is a chronic disease progressing over a long period of time, even a slight increase of BACE1 expression may have a profound effect on Aβ accumulation. We describe a previously unknown mechanism that negatively regulates BACE1 and BACE1-AS expression and demonstrate its pivotal role in the progression of Aβ and Tau pathologies and cognitive impairment in two mouse models of AD. Given the recent failures of the clinical trials using enzymatic inhibitors of BACE1, it is critical to explore alternative approaches such as down-regulating BACE1 and BACE1-AS transcription. Our finding that NRF2 negatively regulates BACE1 and BACE1-AS therefore suggests a potential for disease modification by NRF2-activating phytochemicals or synthetic small molecules in AD.
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Sulforaphane improves cognitive function in 5XFAD and 3xTg-AD mouse models.
“Supplementation of NRF2 antioxidative mechanisms using the NRF2 activator sulforaphane improves cognitive function in 5XFAD and 3xTg-AD mouse models [102], providing supporting evidence of the cognitive benefit of added Nrf2 expression beyond that of the native 5XFAD pathology-driven increase.”
From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [102]
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“Supplementation of NRF2 antioxidative mechanisms using the NRF2 activator sulforaphane improves cognitive function in 5XFAD and 3xTg-AD mouse models [102], providing supporting evidence of the cognitive benefit of added Nrf2 expression beyond that of the native 5XFAD pathology-driven increase.”
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- Authors
- Bahn, G., Park, J.-S., Yun, U. J., Lee, Y. J., Choi, Y., Park, J. S., Baek, S. H., Choi, B. Y., Cho, Y. S., Kim, H. K., Han, J., Sul, J. H., Baik, S.-H., Lim, J., Wakabayashi, N., Bae, S. H., Han, J.-W., Arumugam, T. V., Mattson, M. P., & Jo, D.-G.
- Affiliations
- Sungkyunkwan University (KR)
- Johns Hopkins University (US)
- National University of Singapore (SG)
- National Institutes of Health (US)
- University of Pittsburgh (US)
- Yonsei University (KR)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-06-04
- Volume
- 116
- Issue
- 25
- Pages
- 12516-12523
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6589670
- OpenAlex
- W2948544179
- Cited by
- 210
- References
- 53
- Citations by year
- 2026: 19 · 2025: 32 · 2024: 43 · 2023: 33 · 2022: 32 · 2021: 29 · 2020: 21 · 2019: 1
- FWCI
- 14.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Nrf2/ARE pathway, BACE1, Alzheimer's disease, amyloid-beta deposition, tau pathology, cognitive impairment, transcriptional regulation, disease modification, Nrf2 activators, phytochemicals, mouse models of Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Animals, Cognition Disorders, Disease Models, Animal, Gene Expression Regulation, Humans, Mice, Transgenic, Promoter Regions, Genetic, Protein Binding, Sulfoxides, Transcription, Genetic, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Reactive Oxygen Species, Isothiocyanates, NF-E2-Related Factor 2, Mice, Amyloid Precursor Protein Secretases
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