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
BACE1and a BACE1mRNA-stabilizing antisense RNA ( BACE1-AS) are elevated in the brains of AD patients, implicating that dysregulation of BACE1expression plays an important role in AD pathogenesis. We found that nuclear factor erythroid-derived 2-related factor 2 (NRF2/NFE2L2) represses the expression of BACE1and BACE1-ASthrough binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of BACE1and BACE1-ASexpression is independent of redox regulation. NRF2 activation decreases production of BACE1and BACE1-AStranscripts and Aβ production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases BACE1and BACE1-ASexpression and Aβ production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.