Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
The Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
Nat Neurosci. 2023 May;26(5):737-750. doi: 10.1038/s41593-023-01315-6. Epub 2023 Apr 24.
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.
阿尔茨海默病（AD）的病理特征在临床症状出现前数年就已出现，这表明在痴呆发生之前存在认知弹性期。在这里，我们报告称，环状鸟苷酸-腺苷酸合酶（cGAS）的激活通过 I 型干扰素（IFN-I）信号降低肌细胞增强因子 2c（MEF2C）的神经元转录网络，从而降低认知弹性。致病性 tau 通过线粒体 DNA 的细胞质渗漏在小胶质细胞中激活 cGAS 和 IFN-I 反应，部分介导。tau 病小鼠中 Cgas 的基因缺失减少了小胶质细胞 IFN-I 反应，保护了突触完整性和可塑性，并防止了认知障碍，而不会影响致病性 tau 负荷。cGAS 缺失增加，而 IFN-I 激活减少，与 AD 中认知弹性相关的神经元 MEF2C 表达网络。tau 病小鼠中 cGAS 的药理学抑制增强了神经元 MEF2C 转录网络，并恢复了突触完整性、可塑性和记忆，支持靶向 cGAS-IFN-MEF2C 轴以改善对 AD 相关病理损伤的弹性的治疗潜力。
