한빛사 논문
Heejung Chun1,2,3, Hyeonjoo Im3, You Jung Kang4, Yunha Kim3, Jin Hee Shin5, Woojin Won1,6, Jiwoon Lim1, Yeonha Ju1,7,8, Yongmin Mason Park1,7,8, Sunpil Kim1,6, Seung Eun Lee9, Jaekwang Lee2, Junsung Woo2, Yujin Hwang3, Hyesun Cho3,10, Seonmi Jo2,11, Jong-Hyun Park12, Daesoo Kim11, Doo Yeon Kim13, Jeong-Sun Seo10,14, Byoung Joo Gwag5, Young Soo Kim15, Ki Duk Park8,12,16, Bong-Kiun Kaang17, Hansang Cho4,18,19, Hoon Ryu3,20,* and C. Justin Lee1,2,6,7,*
1Center for Cognition and Sociality, Institute for Basic Science, Daejeon, Republic of Korea. 2Center for Glia-Neuron Interaction, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea. 3Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea. 4Department of Mechanical Engineering and Engineering Science, Center for Biomedical Engineering and Science, Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA. 5GNT Pharma Co. Ltd., Yongin, Republic of Korea. 6Korea Uivresity-Korea Institute of Science and Technology, Graduate School of Convergence Technology, Korea University, Seoul, Republic of Korea. 7IBS School, University of Science and Technology, Daejeon, Republic of Korea. 8Neuroscience Program, University of Science and Technology, Daejeon, Republic of Korea. 9Virus Facility, Research Animal Resource Center, Korea Institute of Science and Technology, Seoul, Republic of Korea. 10Precision Medicine Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. 11Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. 12Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Republic of Korea. 13Genetics and Aging Research Unit, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. 14Genomic Institute, Macrogen Inc., Seoul, Republic of Korea. 15Integrated Science and Engineering Division, Department of Pharmacy, and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea. 16Division of Bio-Med Science & Technology, KIST School, Korea University of Science and Technology, Seoul, Republic of Korea. 17School of Biological Sciences, Seoul National University, Seoul, Republic of Korea. 18The Nanoscale Science Program, University of North Carolina at Charlotte, Charlotte, NC, USA. 19Department of Biophysics, Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea. 20Boston University Alzheimer’s Disease Center and Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
*Correspondence to Hoon Ryu or C. Justin Lee.
Abstract
Although the pathological contributions of reactive astrocytes have been implicated in Alzheimer’s disease (AD), their in vivo functions remain elusive due to the lack of appropriate experimental models and precise molecular mechanisms. Here, we show the importance of astrocytic reactivity on the pathogenesis of AD using GiD, a newly developed animal model of reactive astrocytes, where the reactivity of astrocytes can be manipulated as mild (GiDm) or severe (GiDs). Mechanistically, excessive hydrogen peroxide (H2O2) originated from monoamine oxidase B in severe reactive astrocytes causes glial activation, tauopathy, neuronal death, brain atrophy, cognitive impairment and eventual death, which are significantly prevented by AAD-2004, a potent H2O2 scavenger. These H2O2−-induced pathological features of AD in GiDs are consistently recapitulated in a three-dimensional culture AD model, virus-infected APP/PS1 mice and the brains of patients with AD. Our study identifies H2O2 from severe but not mild reactive astrocytes as a key determinant of neurodegeneration in AD.
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