Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid β plaques.
Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid β plaques.
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DOI：
10.1016/j.immuni.2022.03.018
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发表时间：
2022-05-10
期刊：
影响因子：
32.4
通讯作者：
Cao, Wei
中科院分区：
文献类型：
--
作者：
Roy, Ethan R.;Chiu, Gabriel;Li, Sanming;Propson, Nicholas E.;Kanchi, Rupa;Wang, Baiping;Coarfa, Cristian;Zheng, Hui;Cao, Wei
阿尔茨海默病（AD）中驱动记忆和认知障碍的主要信号仍然难以捉摸。在此，我们揭示了全脑细胞对I型干扰素（IFN-I）的反应，这是一种由淀粉样蛋白β斑块异常引起的先天免疫细胞因子，并在小鼠淀粉样变性模型中研究了它们在与AD相关的认知和神经病理学中的作用。使用命运映射报告系统跟踪细胞对IFN-I的反应，我们在小胶质细胞和其他细胞类型中检测到稳健的Aβ病理依赖性IFN-I激活。长期阻断IFN-I受体（IFNAR）挽救了记忆和突触缺陷，并导致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Ifnar 1缺失通过选择性吞噬减弱突触后末端的损失，而神经Ifnar 1缺失恢复突触前末端并减少斑块积聚。总的来说，IFN-I信号转导代表了AD神经炎症网络中的关键模块，并提示对记忆和认知有害的协调细胞状态。导致阿尔茨海默病（AD）认知障碍的信号仍然难以捉摸。I型干扰素（IFN-I）活化与神经退行性疾病（包括AD）有关。使用细胞命运映射、受体阻断和条件性缺失模型，Roy等人证明了不同脑细胞类型（包括小胶质细胞和神经细胞）中的IFN-I信号传导严重影响突触并导致AD模型中的认知障碍。
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. The signals that drive cognitive impairment in Alzheimer’s disease (AD) remain elusive. Type I interferon (IFN-I) activation is implicated in neurodegenerative conditions, including AD. Using cellular fate-mapping, receptor blockade, and conditional deletion models, Roy et al. demonstrate that IFN-I signaling in different brain cell types, including microglia and neural cells, critically affects synapses and causes cognitive impairment in an AD model.
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影响因子：
16.2
作者：
Cheadle L;Rivera SA;Phelps JS;Ennis KA;Stevens B;Burkly LC;Lee WA;Greenberg ME
通讯作者：
Greenberg ME
DOI：
10.1073/pnas.1206923109
发表时间：
2012-09-04
影响因子：
11.1
作者：
Di Domizio, Jeremy;Dorta-Estremera, Stephanie;Cao, Wei
通讯作者：
Cao, Wei
DOI：
10.3791/50326
发表时间：
2013-05-12
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
DeVos SL;Miller TM
通讯作者：
Miller TM
影响因子：
5.3
作者：
DeVos, Sarah L.;Goncharoff, Dustin K.;Miller, Timothy M.
通讯作者：
Miller, Timothy M.
影响因子：
32.4
作者：
Filipello, Fabia;Morini, Raffaella;Matteoli, Michela
通讯作者：
Matteoli, Michela