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

阿尔茨海默病中 mtDNA 渗漏和 STING 依赖性小胶质细胞先天免疫反应

• 批准号: 10346449
• 负责人: Heng Du
• 金额: $ 47.49万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10346449
• 关键词: Adaptor Signaling Protein; Address; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Animal Disease Models; Apoptotic; Attenuated; BAX gene; Biological Assay; Brain; Brain Injuries; Brain Pathology; Cells; Cognitive deficits; Critical Pathways; Cyclic GMP; Cytosol; DNA; Data; Dementia; Development; Diffuse Lewy Body Disease; Disease; Down Syndrome; Extravasation; Gene Activation; Gene Expression Profile; Golgi Apparatus; Hippocampus (Brain); Immune; Impaired cognition; Inflammation Mediators; Inflammatory; Innate Immune Response; Interferons; Learning; Light; Link; Mediating; Memory; Messenger RNA; Microglia; Mitochondria; Mitochondrial DNA; Morphology; Mus; Myelogenous; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oxidative Stress; Pathologic; Pathway interactions; Patients; Phagocytosis; Phenotype; Phosphorylation; Pilot Projects; Preventive; Production; Regulation; Reporting; Role; Senile Plaques; Shapes; Signal Transduction; Source; Sterility; Stimulator of Interferon Genes; Stress; Synapses; Testing; Voltage-Dependent Anion Channel; Western Blotting; abeta accumulation; abeta deposition; aging population; antiviral immunity; base; behavior test; mitochondrial dysfunction; mitochondrial permeability transition pore; neuroinflammation; novel; novel strategies; sensor; transcriptomics; treatment strategy

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.

项目摘要 以进行性认知能力下降为特征，阿尔茨海默氏病（AD）是最常见的痴呆类型， 小胶质细胞的炎症激活是 阿尔茨海默氏病（AD）并导致大脑损害。但是，介导的基本机制 尚不完全了解Aβ丰富环境中的小胶质细胞炎症激活。干扰素的刺激器 基因（STING）是一种先天免疫衔接蛋白，它绝对由髓样生物的细胞表达 包括小胶质细胞。尽管在基于干扰素的抗病毒免疫中起着作用，但最近的研究表明 刺激信号传导对非通信疾病中炎症损害的重要贡献。循环GMP- AMP（CGAMP）合酶（CGA）是胞质DNA传感器，并通过sting来促进干扰素 炎症介体的信号传导和产生。内源性DNA的胞质积累尤其 线粒体DNA（mtDNA）片段构成了内源性“无菌”激活因子的重要来源 CGAS插曲信号传导。在我们对患者和具有广告样的AD动物模型的初步研究中 淀粉样病，我们观察到小胶质细胞的刺激活性增加，这导致了早期小胶质激活 在5xfad小鼠中。此外，来自患者和5xFAD小鼠的小胶质细胞表现出胞质mtDNA 积累; CGAS的缺乏减弱了5xFAD小鼠的小胶质细胞刺激激活，这意味着 CGA与STING活化的胞质mtDNA感测。最后，我们的数据表明小胶质细胞 Aβ环境中的线粒体应激可能导致mtDNA的不稳定性和渗入细胞质。因此，我们 假设通过CGA通过胞质mtDNA触发的小胶质细胞刺激信号传导有助于Aβ- 诱导的小胶质细胞激活，最终在AD中的神经炎症和神经元应力。在这里，我们的目标是 在5XFAD小鼠中建立小胶质细胞活性和小胶质激活之间的联系。接下来，我们会的 确定小胶质细胞激活对小胶质细胞失调相关的大脑损害的贡献 在5xfad小鼠中。此外，我们将解决介导富含Aβ中小胶质细胞mtDNA释放的机制 环境并确定mtDNA泄漏对于激活小胶质CGAS插入信号的重要性 在Aβ丰富的环境中。综上所述，这项研究的结果将回答有关刺痛的重要问题 塑造小胶质表型，并提出一种新型的小胶质激活的线粒体机制 用于治疗AD的新途径。