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)的特征是淀粉样蛋白(Aβ，Aβ)在斑块和 神经纤维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， 它们共同导致神经退化和认知障碍。临床和临床前研究都有 提示神经炎症，特别是异常和慢性小胶质细胞的激活是AD的主要组成部分 病因学。先天免疫是宿主抵御入侵病原体和有害物质的第一道防线。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 和胞内小泡，以及核苷酸传感器，如胞浆DNA的环GMP-AMP合成酶(CGAS)。 这些先天信号通路的激活触发了炎性细胞因子的产生，并 干扰素，并通过激活大量干扰素刺激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的，通常可以被宿主分子激活。 在损伤和疾病中；然而，它们在衰老中对神经炎症和AD发病的贡献仍然存在 开发不足。 我们的中心假设是，小胶质细胞中天然免疫的慢性激活是一个基本的基础 神经炎症的机制，可由淀粉样蛋白和/或感染共同触发，以及cGAS- STING介导的先天免疫是AD发生发展过程中的一个重要生物学过程。我们的 初步研究表明，阿尔茨海默病死后脑组织样本胞浆dsDNA水平升高， 5xFAD小鼠模型，与cGAS-STING通路激活密切相关。更重要的是，cGAS 基因敲除小鼠可改善5xFAD模型中的神经炎症和淀粉样蛋白病理。 用刺痛抑制剂H-151进行治疗。为了更好地了解阿尔茨海默病中的cGAS-STING通路， 我们现在建议研究：1)cGAS依赖的神经炎症调节体外使用三细胞 IPSC来源的细胞培养系统，以及cGAS和STING抑制的AD动物模型的发病机制； 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衍生的脑器官模型，包括大脑和脉络丛器官，AT信号和 转录水平；3)HSV1感染在Eoad和Load小鼠模型中AD样发病机制中的作用。 通过这些研究，我们希望对cGAS刺痛的先天免疫有更深入的了解。 中枢神经系统感染、炎症和AD发病机制中的途径，为了解感染性疾病提供新的见解 阿尔茨海默病和相关痴呆(ADRD)的病因。