mtDNA leakage and STING-dependent microglial innate immune response in Alzheimer's disease

项目总结 以进行性认知衰退为特征的阿尔茨海默病(AD)是最常见的痴呆症类型， 主要影响老龄化人口。小胶质细胞的炎性激活是其早期病理特征 阿尔茨海默病(AD)，并导致脑损伤。然而，调解的潜在机制 在富含β的环境中，小胶质细胞的炎症激活尚不完全清楚。干扰素刺激物 基因(STING)是一种天然的免疫调节蛋白，在髓系细胞中大量表达。 包括小胶质细胞。尽管它在基于干扰素的抗病毒免疫中发挥作用，但最近的研究揭示了 非传染性疾病中刺痛信号在炎性损伤中的重要作用。环状GMP- AMP(CGAMP)合成酶(CGAS)是一种胞质DNA传感器，通过STIN传递信号来促进干扰素 炎症介质的信号和产生。胞浆内尤其是内源DNA的积累 线粒体DNA(MtDNA)片段是内源性“不育”激活剂的重要来源 CCAS-STING信令。在我们对患者和类AD动物模型的初步研究中 淀粉样变性，我们观察到小胶质细胞刺痛活性增加，这有助于早期小胶质细胞的激活。 在5xFAD小鼠中。此外，患者和5xFAD小鼠的小胶质细胞显示胞浆mtdna。 CGAS的蓄积和缺乏可减弱5xFAD小鼠的小胶质细胞刺痛活性，提示 CGAS检测胞质线粒体DNA与刺激性的关系。最后，我们的数据表明，小胶质细胞 β环境中的线粒体应激可能导致线粒体DNA的不稳定和泄漏到细胞质中。因此，我们 假设cGAS通过胞浆mtDNA感应触发的小胶质细胞刺痛信号参与了β- 诱导小胶质细胞激活，最终导致阿尔茨海默病的神经炎症和神经元应激。在这里，我们的目标是 在5xFAD小鼠中建立小胶质细胞刺痛活性和小胶质细胞激活之间的联系。接下来，我们将 确定小胶质细胞刺痛激活在小胶质细胞松弛相关脑损伤中的作用 在5xFAD小鼠中。此外，我们还将探讨在富含β的细胞中介导小胶质细胞线粒体DNA释放的机制 并确定mtDNA泄漏对激活小胶质细胞cGAS-STING信号的重要性 在一个富含β的环境中。综上所述，这项研究的结果将回答有关刺痛的重要问题 形成小胶质细胞表型，并将提出一种新的线粒体小胶质细胞激活和 治疗阿尔茨海默病的新途径。

PROJECT SUMMARY Characterized by progressive cognitive decline, Alzheimer's disease (AD) is the most common type of dementia, primarily affecting the aging population. Inflammatory activation of microglia is an early pathological feature of Alzheimer’s disease (AD) and contributes to brain damages. However, the underlying mechanisms that mediate microglial inflammatory activation in Aβ-rich milieus are not completely understood. Stimulator of interferon genes (STING) is an innate immune adaptor protein that is abundantly expressed by cells of myeloid origin including microglia. Despite its roles in interferon-based antiviral immunity, recent studies have revealed an important contribution of STING signaling to inflammatory damages in non-communicable disorders. cyclic GMP- AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor and signals through STING to promote interferon signaling and production of inflammatory mediators. Cytosolic accumulation of endogenous DNA especially mitochondrial DNA (mtDNA) fragments constitutes an important source of endogenous “sterile” activator of cGAS-STING signaling. In our preliminary study on patients and an AD animal model with AD-like amyloidopathy, we observed increased microglial STING activity, which contributed to early microglial activation in 5xFAD mice. In addition, microglia from patients and 5xFAD mice demonstrated cytosolic mtDNA accumulation; and deficiency of cGAS attenuated microglial STING activation in 5xFAD mice, implicating an association of cytosolic mtDNA sensing by cGAS with STING activation. Finally, our data suggest that microglial mitochondrial stress in Aβ milieus may contribute to mtDNA instability and leakage into the cytosol. We therefore hypothesize that microglial STING signaling triggered via cytosolic mtDNA sensing by cGAS contributes to Aβ- induced microglial activation, culminating in neuroinflammation and neuronal stress in AD. Here, we aim to establish a link between microglial STING activity and microglial activation in 5xFAD mice. Next, we will determine the contribution of microglial STING activation to microglial deregulation-associated brain damages in 5xFAD mice. In addition, we will address the mechanisms that mediate microglial mtDNA release in Aβ-rich milieus and determine the importance of mtDNA leakage for the activation of microglial cGAS-STING signaling in Aβ-rich milieus. Taken together, the results from this study will answer important questions about STING in shaping microglial phenotype, and will suggest a novel mitochondrial mechanism of microglial activation and new avenues for the treatment of AD.