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

Authors
 Gahee Bahn  ;  Jong-Sung Park  ;  Ui Jeong Yun  ;  Yoon Jee Lee  ;  Yuri Choi  ;  Jin Su Park  ;  Seung Hyun Baek  ;  Bo Youn Choi  ;  Yoon Suk Cho  ;  Hark Kyun Kim  ;  Jihoon Han  ;  Jae Hoon Sul  ;  Sang-Ha Baik  ;  Jinhwan Lim  ;  Nobunao Wakabayashi  ;  Soo Han Bae  ;  Jeung-Whan Han  ;  Thiruma V. Arumugam  ;  Mark P. Mattson  ;  Dong-Gyu Jo 
Citation
 Proceedings of the National Academy of Sciences of the United States of America, Vol.116(25) : 12516-12523, 2019 
Journal Title
 Proceedings of the National Academy of Sciences of the United States of America 
ISSN
 0027-8424 
Issue Date
2019
Keywords
3xTg-AD mice ; 5xFAD mice ; Alzheimer’s disease ; BACE1 ; NRF2
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.
Full Text
https://www.pnas.org/content/116/25/12516.long
DOI
10.1073/pnas.1819541116
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Bae, Soo Han(배수한) ORCID logo https://orcid.org/0000-0002-8007-2906
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/170953
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