biostudies-literatureUnknown116(25)Bahn GBACE1 is the rate-limiting enzyme for amyloid-β peptides (Aβ) generation, a key event in the pathogenesis of Alzheimer's disease (AD). By an unknown mechanism, levels of <i>BACE1</i> and a <i>BACE1</i> mRNA-stabilizing antisense RNA (<i>BACE1-AS</i>) are elevated in the brains of AD patients, implicating that dysregulation of <i>BACE1</i> 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 <i>BACE1</i> and <i>BACE1-AS</i> through binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of <i>BACE1</i> and <i>BACE1-AS</i> expression is independent of redox regulation. NRF2 activation decreases production of <i>BACE1</i> and <i>BACE1-AS</i> transcripts and Aβ production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases <i>BACE1</i> and <i>BACE1-AS</i> expression and Aβ production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.Proceedings of the National Academy of Sciences of the United States of America12516-12523https://www.ebi.ac.uk/biostudies/studies/S-EPMC6589670biostudies-literatureNRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer's models.PMC6589670Yun UJKim HKMattson MPBae SHArumugam TVBahn GLee YJBaik SHPark JSSul JHBaek SHCho YSWakabayashi NChoi YLim JHan JJo DGChoi BYHan JWfalseNRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer's models.BACE1 is the rate-limiting enzyme for amyloid-β peptides (Aβ) generation, a key event in the pathogenesis of Alzheimer's disease (AD). By an unknown mechanism, levels of <i>BACE1</i> and a <i>BACE1</i> mRNA-stabilizing antisense RNA (<i>BACE1-AS</i>) are elevated in the brains of AD patients, implicating that dysregulation of <i>BACE1</i> 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 <i>BACE1</i> and <i>BACE1-AS</i> through binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of <i>BACE1</i> and <i>BACE1-AS</i> expression is independent of redox regulation. NRF2 activation decreases production of <i>BACE1</i> and <i>BACE1-AS</i> transcripts and Aβ production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases <i>BACE1</i> and <i>BACE1-AS</i> expression and Aβ production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.2019-01-01T00:00:00Z2019 Jun2025-04-22T00:29:07.018Z2025-04-05T19:33:57.931ZS-EPMC65896703116442010.1073/pnas.1819541116