NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer's models.

Abstract

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.