Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 25, Pages 12516-12523Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1819541116
Keywords
NRF2; BACE1; Alzheimer's disease; 3xTg-AD mice; 5xFAD
Categories
Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF)
- Ministry of Education, Science and Technology, Republic of Korea [2019R1A2C3011422, 2012R1A5A2A28671860, 2017M3C7A1048268, 2018M3C7A1021851]
- Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH)
- National Research Foundation of Korea [2019R1A2C3011422, 2017M3C7A1048268] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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BACE1 is the rate-limiting enzyme for amyloid-p peptides (An) generation, a key event in the pathogenesis of Alzheimer's disease (AD). By an unknown mechanism, levels of BACE1 and a BACE1 mRNA-stabilizing antisense RNA (BACE1-AS) are elevated in the brains of AD patients, implicating that dysregulation of BACE1 expression plays an important role in AD pathogenesis. We found that nuclear factor erythroid-derived 2-related factor 2 (NRF2/ NFE2L2) represses the expression of BACE1 and BACE1-AS through binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of BACE1 and BACE1-AS expression is independent of redox regulation. NRF2 activation decreases production of BACE1 and BACE1-AS transcripts and A beta production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases BACE1 and BACE1-AS expression and A beta production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.
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