1. NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer's models.
- Author
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Bahn, Gahee, Jong-Sung Park, Ui Jeong Yun, Yoon Jee Lee, Yuri Choi, Jin Su Park, Seung Hyun Baek, Bo Youn Choi, Yoon Suk Cho, Hark Kyun Kim, Jihoon Han, Jae Hoon Sul, Sang-Ha Baik, Jinhwan Lim, Nobunao Wakabayashi, Soo Han Bae, Jeung-Whan Han, Arumugam, Thiruma V., Mattson, Mark P., and Dong-Gyu Jo
- Subjects
ANTISENSE RNA ,ALZHEIMER'S disease ,MICE - Abstract
BACE1 is the rate-limiting enzyme for amyloid-ß peptides (Aß) 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 Aß production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases BACE1 and BACE1-AS expression and Aß production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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