小柯机器人

美国威尔康奈尔医学Li Gan小组发现在小胶质细胞中，Tau激活的cGAS-IFN通路降低了MEF2C介导的认知灵活性。该研究于2023年4月24日发表于国际学术期刊《自然—神经科学》杂志。

研究人员发现环GMP-AMP合酶（cGAS）激活通过I型干扰素（IFN-I）信号传导减少肌细胞增强因子2c（MEF2C）的神经元转录网络来降低认知弹性。致病性tau激活小胶质细胞中的cGAS和IFN-I，部分是由线粒体DNA进入胞质介导的。敲除小鼠的Cgas减弱了小胶质细胞的IFN-I反应，保留了突触的完整性和可塑性，并在不影响致病性tau负荷的情况下预防认知障碍。

cGAS缺失增加，而IFN-I的激活降低，神经元MEF2C表达网络与阿尔茨海默病（AD）的认知弹性相关。利用药物抑制小鼠cGAS增强了神经元MEF2C转录网络并恢复了突触完整性、可塑性和记忆力，这些发现表明靶向cGAS-IFN-MEF2C轴是提高AD相关病理损伤恢复力的潜在方法。

据悉，AD的病理特征比临床症状早几年出现，这表明在痴呆发生前有一段时间的认知恢复力。

附：英文原文

Title: Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience

Author: Udeochu, Joe C., Amin, Sadaf, Huang, Yige, Fan, Li, Torres, Eileen Ruth S., Carling, Gillian K., Liu, Bangyan, McGurran, Hugo, Coronas-Samano, Guillermo, Kauwe, Grant, Mousa, Gergey Alzaem, Wong, Man Ying, Ye, Pearly, Nagiri, Ravi Kumar, Lo, Iris, Holtzman, Julia, Corona, Carlo, Yarahmady, Allan, Gill, Michael T., Raju, Ravikiran M., Mok, Sue-Ann, Gong, Shiaoching, Luo, Wenjie, Zhao, Mingrui, Tracy, Tara E., Ratan, Rajiv R., Tsai, Li-Huei, Sinha, Subhash C., Gan, Li

Issue&Volume: 2023-04-24

Abstract: Pathological hallmarks of Alzheimer’s disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP–AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS–IFN–MEF2C axis to improve resilience against AD-related pathological insults.

DOI: 10.1038/s41593-023-01315-6

Source: https://www.nature.com/articles/s41593-023-01315-6

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex