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 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.

authors

Bahn G,Park JS,Yun UJ,Lee YJ,Choi Y,Park JS,Baek SH,Choi BY,Cho YS,Kim HK,Han J,Sul JH,Baik SH,Lim J,Wakabayashi N,Bae SH,Han JW,Arumugam TV,Mattson MP,Jo DG

doi

10.1073/pnas.1819541116

subject

Has Abstract

pub_date

2019-06-18 00:00:00

pages

12516-12523

issue

25

eissn

0027-8424

issn

1091-6490

pii

1819541116

journal_volume

116

pub_type

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