The principal signals that drive memory and cognitive impairment in Alzheimer’s disease (AD) remain elusive. Here, we revealed brain-wide cellular reactions to type I interferon (IFN-I), an innate immune cytokine aberrantly elicited by amyloid β plaques, and examined their role in cognition and neuropathology relevant to AD in a murine amyloidosis model. Using a fate-mapping reporter system to track cellular responses to IFN-I, we detected robust, Aβ-pathology-dependent IFN-I activation in microglia and other cell types. Long-term blockade of IFN-I receptor (IFNAR) rescued both memory and synaptic deficits and resulted in reduced microgliosis, inflammation, and neuritic pathology. Microglia-specific Ifnar1 deletion attenuated the loss of post-synaptic terminals by selective engulfment, whereas neural Ifnar1 deletion restored pre-synaptic terminals and decreased plaque accumulation. Overall, IFN-I signaling represents a critical module within the neuroinflammatory network of AD and prompts concerted cellular states that are detrimental to memory and cognition.

阿尔茨海默病（AD）中导致记忆和认知障碍的主要信号仍然难以捉摸。在这里，我们揭示了对 I 型干扰素 (IFN-I) 的全脑细胞反应，I 型干扰素是一种由 β 淀粉样斑块异常引发的先天免疫细胞因子，并在小鼠淀粉样变性模型中检查了它们在与 AD 相关的认知和神经病理学中的作用。使用命运图谱报告系统追踪细胞对 IFN-I 的反应，我们在小胶质细胞和其他细胞类型中检测到了强大的、Aβ 病理依赖的 IFN-I 激活。长期阻断 IFN-I 受体 (IFNAR) 可挽救记忆和突触缺陷，并减少小胶质细胞增生、炎症和神经炎病理。小胶质细胞特异性Ifnar1缺失通过选择性吞噬减轻了突触后末梢的损失，而神经性Ifnar1缺失则恢复了突触前末梢并减少了斑块积累。总体而言，IFN-I 信号传导代表 AD 神经炎症网络中的关键模块，并促进不利于记忆和认知的协调细胞状态。