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 and a mRNA-stabilizing antisense RNA () are elevated in the brains of AD patients, implicating that dysregulation of 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 and through binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of and expression is independent of redox regulation. NRF2 activation decreases production of and transcripts and Aβ production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases and expression and Aβ production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.
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| http://dx.doi.org/10.1073/pnas.1819541116 | DOI Listing |
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