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

被引：198

作者：

Bahn, Gahee ^{[1
]}

Park, Jong-Sung ^{[1
,2
]}

Yun, Ui Jeong ^{[1
,3
]}

Lee, Yoon Jee ^{[1
]}

Choi, Yuri ^{[1
]}

Park, Jin Su ^{[1
,4
]}

Baek, Seung Hyun ^{[1
]}

Choi, Bo Youn ^{[1
]}

Cho, Yoon Suk ^{[1
]}

Kim, Hark Kyun ^{[1
]}

Han, Jihoon ^{[1
]}

Sul, Jae Hoon ^{[1
]}

Baik, Sang-Ha ^{[1
,5
]}

Lim, Jinhwan ^{[6
,7
]}

Wakabayashi, Nobunao ^{[8
]}

Bae, Soo Han ^{[9
,10
]}

Han, Jeung-Whan ^{[1
]}

Arumugam, Thiruma V. ^{[1
,5
]}

Mattson, Mark P. ^{[11
]}

Jo, Dong-Gyu ^{[1
,4
,12
]}

机构：

[1] Sungkyunkwan Univ, Sch Pharm, Suwon 16419, South Korea

[2] Johns Hopkins Med Sch, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA

[3] Sungkyunkwan Univ, Dept Food Sci & Biotechnol, Suwon 16419, South Korea

[4] Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Dept Hlth Sci & Technol, Seoul 06351, South Korea

[5] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117593, Singapore

[6] Univ Calif Irvine, Dept Med, Irvine, CA 92697 USA

[7] NIA, Lab Expt Gerontol, Intramural Res Program, Baltimore, MD 21224 USA

[8] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15261 USA

[9] Yonsei Univ, Coll Med, Severance Biomed Sci Inst, Seoul 03722, South Korea

[10] Yonsei Univ, Coll Med, Yonsei Biomed Res Inst, Seoul 03722, South Korea

[11] NIA, Lab Neurosci, NIH, Baltimore, MD 21224 USA

[12] Sungkyunkwan Univ, Biomed Inst Convergence, Suwon 16419, South Korea

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2019年 / 116卷 / 25期

基金：

新加坡国家研究基金会; 美国国家卫生研究院;

关键词：

NRF2; BACE1; Alzheimer's disease; 3xTg-AD mice; 5xFAD; SEQUENCE-SPECIFIC CONTROL; BETA-SECRETASE; ENZYMATIC-ACTIVITY; PARTIAL REDUCTION; NONCODING RNA; DISEASE; APP; ANTIOXIDANT; MICE; INHIBITOR;

D O I：

10.1073/pnas.1819541116

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

BACE1 is the rate-limiting enzyme for amyloid-p peptides (An) 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 A beta production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases BACE1 and BACE1-AS expression and A beta production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.

引用

页码：12516 / 12523

页数：8

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