한빛사 논문
Gahee Bahna,1, Jong-Sung Parka,b,1, Ui Jeong Yuna,c,1, Yoon Jee Leea, Yuri Choia, Jin Su Parka,d, Seung Hyun Baeka, Bo Youn Choia, Yoon Suk Choa, Hark Kyun Kima, Jihoon Hana, Jae Hoon Sula, Sang-Ha Baika,e, Jinhwan Limf,g, Nobunao Wakabayashih, Soo Han Baei,j, Jeung-Whan Hana, Thiruma V. Arumugama,e, Mark P. Mattsonk,2, and Dong-Gyu Joa,d,l,2
a School of Pharmacy, Sungkyunkwan University, 16419 Suwon, Republic of Korea; b Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical School, Baltimore, MD 21205; c Department of Food Science and Biotechnology, Sungkyunkwan University, 16419 Suwon, Republic of Korea; d Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, 06351 Seoul, Republic of Korea; e Department of Physiology, Yong Loo Lin School Medicine, National University of Singapore, 117593 Singapore; f Department of Medicine, University of California, Irvine, CA 92697; g Laboratory of Experimental Gerontology, National Institute on Aging Intramural Research Program, Baltimore, MD 21224; h Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261; i Severance Biomedical Science Institute, Yonsei University College of Medicine, 03722 Seoul, Republic of Korea; j Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 03722 Seoul, Republic of Korea; k Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; and l Biomedical Institute for Convergence, Sungkyunkwan University, 16419 Suwon, Republic of Korea
1 G.B., J.-S.P., and U.J.Y. contributed equally to this work.
2To whom correspondence may be addressed.
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.
NRF2, BACE1, Alzheimer’s disease, 3xTg-AD mice, 5xFAD mice
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