cGAS-STING mediated neuroinflammation in Alzheimer's disease

cGAS-STING 介导的阿尔茨海默病神经炎症

• 批准号: 10900996
• 负责人: Weiming Yuan
• 金额: $ 82.62万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10900996
• 关键词: Acceleration; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Animal Model; Astrocytes; Autopsy; Biological Process; Blood Vessels; Brain; Cell surface; Cells; Central Nervous System Infections; Cerebrum; Chronic; Clinical Research; Complex; Conditioned Culture Media; Cyclic GMP; DNA; Dementia; Deposition; Development; Disease; Double Stranded DNA Virus; Drug Design; Early Onset Alzheimer Disease; Etiology; Functional disorder; Genes; Genetic; Genetic Transcription; Genome; Herpes Simplex Infections; Herpesviridae; Herpesvirus 1; Heterogeneity; Host Defense; Human; Immune; Immune response; Immune signaling; Impaired cognition; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Injury; Innate Immune Response; Interferons; Invaded; Knock-in; Knock-out; Knockout Mice; Link; Mediating; Metabolism; Microglia; Mitochondria; Modeling; Molecular; Natural Immunity; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Nucleotides; Organoids; Pathogenesis; Pathway interactions; Patients; Pattern recognition receptor; Phenotype; Play; Production; Role; Sampling; Senile Plaques; Signal Pathway; Signal Transduction; Simplexvirus; Stimulator of Interferon Genes; Stress; Structure of choroid plexus; Surveys; Synapses; System; Toll-like receptors; Vesicle; Virus; Virus Diseases; abeta accumulation; abeta oligomer; age related; amyloid induced neuroinflammation; amyloid pathology; brain cell; cell type; cytokine; ds-DNA; hyperphosphorylated tau; in vivo; induced pluripotent stem cell; inducible gene expression; inhibitor; innate immune pathways; insight; mouse model; neural; neuroinflammation; neurovascular; new therapeutic target; pathogen; pharmacologic; preclinical study; response; response to injury; sensor; tau Proteins; tool; transcriptomics

Abstract: Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) in plaques and hyperphosphorylated tau in neurofibrillary tangles, as well as neurovascular dysfunctions and neuroinflammation, which together result in neurodegeneration and cognitive impairment. Both clinical and preclinical studies have indicated that neuroinflammation, particularly abnormal and chronic microglia activation, is a major part of AD etiology. Innate immunity is the first line of host defense against invading pathogens and harmful substance. It consists evolutionarily conserved pattern recognition receptors, including Toll-like receptors on the cell surface and intracellular vesicles, and nucleotide sensors such as cyclic GMP-AMP synthase (cGAS) for cytosolic DNA. The activation of these innate signaling pathways triggers the production of inflammatory cytokines and interferons, and further amplifies the immune response by activating a large array of interferon-stimulated genes. Interestingly, the innate immune responses are not always specific, and can often be activated by host molecules in injuries and diseases; however, their contributions to neuroinflammation and AD pathogenesis in aging remain underexplored. Our central hypothesis is that chronic activation of innate immunity in microglia is a fundamental underlying mechanism for neuroinflammation, which can be collectively triggered by amyloid and/or infections, and cGAS- STING mediated innate immunity is a critical biological process in the development and progression of AD. Our preliminary studies showed that cytosolic dsDNA levels were increased in AD post-mortem brain samples and 5xFAD mouse model, which is tightly associated with cGAS-STING pathway activation. More importantly, cGAS knockout mice ameliorated the neuroinflammation and amyloid pathologies in the 5xFAD model, which can be mimicked by a treatment with STING inhibitor H-151. For a better understanding of cGAS-STING pathway in AD, we now propose to study: 1) cGAS-STING dependent modulation of neuroinflammation in vitro using a tri-cellular culture system with iPSC-derived cells, and AD pathogenesis in animal models with cGAS and STING inhibitions; 2) the impact of herpes simplex virus (HSV-1) infection on cGAS-STING pathway and neuroinflammation using iPSC-derived brain organoid models including cerebral and choroid plexus organoids, at signaling and transcriptomic levels; 3) the effect of HSV1 infection on AD-like pathogenesis in EOAD and LOAD mouse models. Through these studies, we hope to achieve an in-depth understanding of the cGAS-STING innate immune pathway in CNS infection, inflammation and AD pathogenesis, and provide new insights into the infectious etiology of AD and related dementia (ADRD).

摘要： 阿尔茨海默病（AD）的特征在于斑块中淀粉样蛋白-β（Aβ）的积累， 神经血管缠结中的过度磷酸化tau，以及神经血管功能障碍和神经炎症， 共同导致神经退化和认知障碍。临床和临床前研究都有 表明神经炎症，特别是异常和慢性小胶质细胞活化，是AD的主要部分 病因学天然免疫是机体抵御病原体和有害物质入侵的第一道防线。它 由进化上保守的模式识别受体组成，包括细胞表面的Toll样受体 和胞内囊泡，以及核苷酸传感器，如用于胞质DNA的环GMP-AMP合酶（cGAS）。 这些先天信号通路的激活触发炎性细胞因子的产生， 干扰素，并通过激活大量干扰素刺激的基因进一步放大免疫反应。 有趣的是，先天免疫反应并不总是特异性的，并且通常可以被宿主分子激活 然而，它们在衰老过程中对神经炎症和AD发病机制的作用仍然存在， 探索不足 我们的中心假设是，小胶质细胞先天免疫的慢性激活是一个基本的潜在因素， 神经炎症的机制，其可以由淀粉样蛋白和/或感染共同触发，以及cGAS- STING介导的先天免疫是AD发生和发展的关键生物学过程。我们 初步研究表明，AD死后脑样品中胞质dsDNA水平增加， 5xFAD小鼠模型，其与cGAS-STING途径活化紧密相关。更重要的是，CGAS 基因敲除小鼠改善了5xFAD模型中的神经炎症和淀粉样蛋白病理学，这可能是 通过用STING抑制剂H-151处理来模拟。为了更好地理解AD中的cGAS-STING通路， 我们现在提出研究：1）使用三细胞免疫印迹技术在体外对神经炎症的cGAS-STING依赖性调节。 具有iPSC衍生细胞的培养系统，以及具有cGAS和STING抑制的动物模型中的AD发病机制; 2)单纯疱疹病毒（HSV-1）感染对cGAS-STING通路和神经炎症的影响 iPSC衍生的脑类器官模型，包括脑和脉络丛类器官，在信号传导和 转录组水平; 3）HSV 1感染对EOAD和LOAD小鼠模型中AD样发病机制的影响。 通过这些研究，我们希望能够对cGAS-STING先天免疫有更深入的了解， 通路在中枢神经系统感染，炎症和AD发病机制，并提供新的见解，感染性 AD和相关痴呆（ADRD）的病因学。