Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice
Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice
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腹腔注射 IFN-γ 可恢复小胶质细胞自噬，促进淀粉样蛋白 -β 清除并改善 APP/PS1 小鼠的认知能力
DOI：
10.1038/s41419-020-2644-4
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发表时间：
2020-06-08
影响因子：
9
通讯作者：
Yao, Zhibin
中科院分区：
文献类型：
--
作者：
He, Zitian;Yang, Yunjie;Yao, Zhibin
自噬是哺乳动物细胞中维持细胞稳态和功能的主要自降解过程。自噬功能障碍发生在阿尔茨海默病（AD）的早期发病机制中，并直接调节淀粉样蛋白-β（Aβ）代谢。尽管已证明细胞因子 IFN-γ 可以增强巨噬细胞系中的自噬，但信号级联是否与 AD 小鼠模型中的 Aβ 降解有关仍有待阐明。在这里，我们发现，在 AD 小鼠模型 APP/PS1 小鼠中，腹腔注射 IFN-γ 9 天可显着增加 LC3II/I 比率并降低 p62 水平。在体外，IFN-γ通过上调Atg7和Atg5的表达以及LC3II/I比率来保护BV2细胞免受Aβ毒性，而这些保护作用会因干扰Atg5表达而消除。此外，IFN-gamma 可能通过抑制体内和体外的 AKT/mTOR 通路来增强自噬通量。重要的是，使用活体双光子显微镜和荧光染色，我们发现小胶质细胞与外源性IFN-γ和Aβ相互作用，并在APP/PS1;CX3CR1-GFP(+/-)小鼠中包围Aβ。此外，IFN-γ治疗降低了皮质和海马体中的Aβ斑块负荷，并挽救了APP/PS1小鼠的认知缺陷。我们的数据表明，外周注射 IFN-γ 可以恢复小胶质细胞自噬，从而诱导大脑 Aβ 的吞噬作用，这代表了使用外源性 IFN-γ 治疗 AD 的潜在治疗方法。
Autophagy is a major self-degradative process that maintains cellular homeostasis and function in mammalian cells. Autophagic dysfunction occurs in the early pathogenesis of Alzheimer's disease (AD) and directly regulates amyloid-beta (A beta) metabolism. Although it has been proven that the cytokine IFN-gamma enhances autophagy in macrophage cell lines, whether the signaling cascade is implicated in A beta degradation in AD mouse models remains to be elucidated. Here, we found that 9 days of the intraperitoneal administration of IFN-gamma significantly increased the LC3II/I ratio and decreased the level of p62 in APP/PS1 mice, an AD mouse model. In vitro, IFN-gamma protected BV2 cells from A beta toxicity by upregulating the expressions of Atg7 and Atg5 and the LC3II/I ratio, whereas these protective effects were ablated by interference with Atg5 expression. Moreover, IFN-gamma enhanced autophagic flux, probably through suppressing the AKT/mTOR pathway both in vivo and in vitro. Importantly, using intravital two-photon microscopy and fluorescence staining, we found that microglia interacted with exogenous IFN-gamma and A beta, and surrounded A beta in APP/PS1;CX3CR1-GFP(+/-) mice. In addition, IFN-gamma treatment decreased the A beta plaque load in the cortex and hippocampus and rescued cognitive deficits in APP/PS1 mice. Our data suggest a possible mechanism by which the peripheral injection of IFN-gamma restores microglial autophagy to induce the phagocytosis of cerebral A beta, which represents a potential therapeutic approach for the use of exogenous IFN-gamma in AD.