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

다국어 초록 (Multilingual Abstract)

<P><B>Significance</B></P><P>Considering that Alzheimer’s disease (AD) is a chronic disease progressing over a long period of time, even a slight increase of <I>BACE1</I> expression may have a profound effect on Aβ accumulation. We describe a previously unknown mechanism that negatively regulates <I>BACE1</I> and <I>BACE1-AS</I> expression and demonstrate its pivotal role in the progression of Aβ and Tau pathologies and cognitive impairment in two mouse models of AD. Given the recent failures of the clinical trials using enzymatic inhibitors of BACE1, it is critical to explore alternative approaches such as down-regulating <I>BACE1</I> and <I>BACE1-AS</I> transcription. Our finding that NRF2 negatively regulates BACE1 and BACE1-AS therefore suggests a potential for disease modification by NRF2-activating phytochemicals or synthetic small molecules in AD.</P><P>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.</P>