Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer’s disease via H2O2-production

Although 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 model and precise molecular mechanisms. Here, we showed have shown the importance of astrocytic reactivity on the pathogenesis of AD, using GiD, a newly developed animal model of reactive astrocytes, in which the reactivity of astrocytes can be manipulated as mild (GiDm) or severe (GiDs). Mechanistically, excessive H2O2 originated from monoamine oxidase B (MAO-B) in severe reactive astrocytes caused glial activation, tauopathy, neuronal death, brain atrophy, cognitive impairment and eventual death, which were significantly prevented by AAD-2004, a potent H2O2 scavenger. These H2O2-induced pathological features of AD in GiDs were consistently recapitulated in 3D-culture AD model, virus-infected APP/PS1 mice and human AD brain. Our study identifies H2O2 from the severe reactive astrocytes, but not mild reactive astrocytes, as a key determinant of neurodegeneration in AD.