학술논문
NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer’s models
Document Type
research-article
Author
Bahn, Gahee; Park, Jong-Sung; Yun, Ui Jeong; Lee, Yoon Jee; Choi, Yuri; Park, Jin Su; Baek, Seung Hyun; Choi, Bo Youn; Cho, Yoon Suk; Kim, Hark Kyun; Han, Jihoon; Sul, Jae Hoon; Baik, Sang-Ha; Lim, Jinhwan; Wakabayashi, Nobunao; Bae, Soo Han; Han, Jeung-Whan; Arumugam, Thiruma V.; Mattson, Mark P.; Jo, Dong-Gyu
Source
Proceedings of the National Academy of Sciences of the United States of America, 2019 Jun . 116(25), 12516-12523.
Subject
Language
English
ISSN
00278424
10916490
10916490
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.