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.

尽管反应性星形胶质细胞的病理学贡献与阿尔茨海默氏病（AD）有关，但由于缺乏合适的实验模型和精确的分子机制，其体内功能仍然难以捉摸。在这里，我们显示了使用GiD（一种新开发的反应性星形胶质细胞的动物模型）在星形胶质细胞的发病机理中星形细胞反应性的重要性，其中星形胶质细胞的反应性可以控制为轻度（GiDm）或严重（GiDs）。从机理上讲，严重反应性星形胶质细胞中源自单胺氧化酶B的过氧化氢（H ₂ O ₂）会引起神经胶质活化，tauopathy，神经元死亡，脑萎缩，认知障碍和最终死亡，而AAD-2004（一种有效的H ₂ O ₂清道夫。这些^ h ₂ Ø ₂ ^-中的GID AD的诱导病理特征是一致的概括在一个三维培养AD模型，病毒感染的APP / PS1小鼠和AD患者的大脑。我们的研究确定了来自严重而非轻度反应性星形胶质细胞的H ₂ O ₂是AD中神经退行性变的关键决定因素。