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

Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12516-12523. doi: 10.1073/pnas.1819541116. Epub 2019 Jun 4.


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 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 Aβ production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases BACE1 and BACE1-AS expression and Aβ production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.

Keywords: 3xTg-AD mice; 5xFAD mice; Alzheimer’s disease; BACE1; NRF2.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism*
  • Cognition Disorders / metabolism*
  • Cognition Disorders / pathology
  • Disease Models, Animal
  • Gene Expression Regulation
  • Humans
  • Isothiocyanates / pharmacology
  • Mice
  • Mice, Transgenic
  • NF-E2-Related Factor 2 / biosynthesis
  • NF-E2-Related Factor 2 / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • Reactive Oxygen Species / metabolism
  • Sulfoxides
  • Transcription, Genetic


  • Amyloid beta-Peptides
  • Isothiocyanates
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Reactive Oxygen Species
  • Sulfoxides
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse
  • sulforaphane