| Literature DB >> 31164420 |
Gahee Bahn1, Jong-Sung Park1,2, Ui Jeong Yun1,3, Yoon Jee Lee1, Yuri Choi1, Jin Su Park1,4, Seung Hyun Baek1, Bo Youn Choi1, Yoon Suk Cho1, Hark Kyun Kim1, Jihoon Han1, Jae Hoon Sul1, Sang-Ha Baik1,5, Jinhwan Lim6,7, Nobunao Wakabayashi8, Soo Han Bae9,10, Jeung-Whan Han1, Thiruma V Arumugam1,5, Mark P Mattson11, Dong-Gyu Jo12,4,13.
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.Entities:
Keywords: 3xTg-AD mice; 5xFAD mice; Alzheimer’s disease; BACE1; NRF2
Year: 2019 PMID： 31164420 PMCID： PMC6589670 DOI： 10.1073/pnas.1819541116
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205