Chun, Heejung Im, Hyeonjoo Kang, You Jung Kim, Yunha Shin, Jin Hee Won, Woojin Lim, Jiwoon Ju, Yeonha Park, Yongmin Mason Kim, Sunpil Lee, Seung Eun Lee, Jaekwang Woo, Junsung Hwang, Yujin Cho, Hyesun Jo, Seonmi Park, Jong-Hyun Kim, Daesoo Kim, Doo Yeon Seo, Jeong-Sun Gwag, Byoung Joo Kim, Young Soo Park, Ki Duk Kaang, Bong-Kiun Cho, Hansang Ryu, Hoon Lee, C. Justin 2024-01-19T16:02:27Z 2024-01-19T16:02:27Z 2021-09-02 2020-12 1097-6256 https://pubs.kist.re.kr/handle/201004/117771 Chun et al. find that a severe model of reactive astrocytes overproduces hydrogen peroxide, leading to the development of Alzheimer's disease-like pathologies, including neurodegeneration, tauopathy and memory impairment. 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. English Nature Publishing Group Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer’s disease via H2O2- production Article 10.1038/s41593-020-00735-y 1 Nature Neuroscience, v.23, no.12, pp.1555 - 1566 Nature Neuroscience 23 12 1555 1566 N scie scopus 000590105700002 2-s2.0-85096041540 Neurosciences Neurosciences & Neurology Article AUTOPHAGY INDUCTION MICROGLIA ABLATION NEURONS GABA MICE GLIA MOUSE MODEL