He Sijia, Li Xin, Mittra Namrata, Bhattacharjee Anindita, Wang Hu, Zhao Shangang, Liu Feng, Han Xianlin
bioRxiv. 2023 Aug 8:2023.08.07.552300. doi: 10.1101/2023.08.07.552300.
Innate immune activation plays a vital role in the development of Alzheimer's disease (AD) and related dementias (ADRD). Among which, the DNA sensing cyclic GMP-AMP synthase (cGAS)- STING pathway has been implicated in diverse aspects of AD progression. In the current study, we showed that the cGAS-STING signaling was up-regulated in AD and this elevation was mainly contributed by the microglial population other than non-microglial cell types in the brain. By establishing an inducible, microglia-specific cGAS knockout mouse model in 5xFAD background, we found that deleting microglial cGAS at the onset of amyloid-β (Aβ) pathology significantly limited plaque formation, and protected mice from Aβ-induced cognitive impairment. Mechanistically, we found cGAS was necessary for plaque-associated microglial enrichment potentially driven by IRF8, and was indispensable for the development of disease-associated microglia (DAM) phenotype. Meanwhile, the loss of microglial cGAS reduced the levels of dystrophic neurites which led to preserved synaptic integrity and neuronal function. Our study provides new insights in understanding the effects of innate immune in AD via a cell-type specific manner, and lays the foundation for potential targeted intervention of the microglial cGAS-STING pathway toward the improvement of AD.
先天性免疫激活在阿尔茨海默病（AD）及相关痴呆症（ADRD）的发展过程中起着至关重要的作用。其中，DNA感应环状GMP-AMP合酶（cGAS）-干扰素基因刺激蛋白（STING）通路涉及AD进展的多个方面。在本研究中，我们发现AD中cGAS-STING信号上调，且这种上调主要由脑内的小胶质细胞群体而非非小胶质细胞类型引起。通过在5xFAD背景下建立一种可诱导的、小胶质细胞特异性cGAS基因敲除小鼠模型，我们发现，在淀粉样β蛋白（Aβ）病理开始时删除小胶质细胞cGAS可显著限制斑块形成，并保护小鼠免受Aβ诱导的认知障碍。从机制上讲，我们发现cGAS对于可能由干扰素调节因子8（IRF8）驱动的斑块相关小胶质细胞富集是必需的，并且对于疾病相关小胶质细胞（DAM）表型的发展是不可或缺的。同时，小胶质细胞cGAS的缺失降低了营养不良性神经突的水平，从而维持了突触完整性和神经元功能。我们的研究为通过细胞类型特异性方式理解先天性免疫在AD中的作用提供了新的见解，并为针对小胶质细胞cGAS-STING通路进行潜在的靶向干预以改善AD奠定了基础。
