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.
Bibliographical noteFunding Information:
IBS-R001-D2 from the Institute for Basic Science from the Ministry of Science (to C.J.L.). This study was also supported by a National Institutes of Health grant no. AG054156, grant no. NRF-2016M3C7A1904233 and grant no. 2E26663 from KIST (to H.R.). This work was supported by the Pioneering Funding Award funded by the Cure Alzheimer’s Fund and the NIH (grant no. AG059236-01A1 to H.C.), by the National Honor Scientist Program (grant no. NRF-2012R1A3A1050385 to B.K.K.) and by The Bio & Medical Technology Development Program (grant no. NRF‐2019M3E5D2A01066259 to D.K.).
This research was supported by the Creative Research Initiative Program, Korean National Research Foundation (NRF) (grant no. 2015R1A3A2066619), Brain Research Program through the NRF funded by the Ministry of Science and ICT (grant nos. 2018M3C7A1056682 and 2018M3C7A1056897), a National Research Council of Science & Technology grant by the Korean government (MSIP) (no. CRC-15-04-KIST), grant no. 2E28411 from the Korean Institute of Science and Technology (KIST) and grant no.
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