cGAS-STING mediated neuroinflammation in Alzheimer's disease

cGAS-STING 介导的阿尔茨海默病神经炎症

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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).

抽象的：阿尔茨海默氏病（AD）的特征是淀粉菌在斑块中的积累和神经原纤维缠结的高磷酸化tau，神经血管功能障碍和神经炎症，共同导致神经退行性和认知障碍。临床和临床前研究都有表明神经炎症，尤其是异常和慢性小胶质细胞激活，是AD的主要部分病因。先天免疫是抵抗入侵病原体和有害物质的第一线防御。它由进化配置的模式识别受体组成，包括细胞表面上的Toll样受体细胞内蔬菜以及核卫星传感器（例如环状GMP-AMP合酶（CGA））用于胞质DNA。这些先天信号通路的激活触发了炎症细胞因子和干扰素，以及通过激活大量干扰素刺激的基因来进一步放大免疫响应。有趣的是，先天免疫调查并不总是具体的，并且通常可以被宿主分子激活受伤和疾病；但是，它们对衰老中神经炎症和AD发病机理的贡献仍然存在尚未得到充实的。我们的核心假设是，小胶质细胞中先天免疫的长期激活是基本的基础神经炎症的机制，可以通过淀粉样蛋白和/或感染统治，以及CGAS- 刺激介导的先天免疫是AD发展和发展的关键生物学过程。我们的初步研究表明，在验尸后大脑样本和 5XFAD小鼠模型，它与CGAS刺途径激活密切相关。更重要的是，CGA 敲除小鼠改善了5xFAD模型中的神经炎症和淀粉样蛋白病理用STING抑制剂H-151的治疗模仿。为了更好地了解AD中的CGAS刺道途径我们现在建议研究：1）使用三细胞的CGAS依赖性调制神经炎症的调制具有IPSC衍生细胞的培养系统，以及具有CGA和刺激性抑制作用的动物模型中的AD发病机理； 2）单纯疱疹病毒（HSV-1）感染对使用CGAS刺激途径和神经炎症的影响 IPSC衍生的脑器官模型，包括大脑和脉络丛器官，在信号和转录组水平； 3）HSV1感染对EOAD和负载小鼠模型中AD样发病机理的影响。通过这些研究，我们希望能够深入了解CGAS sting先天免疫中枢神经系统感染，感染和AD发病机理的途径，并为感染的新见解 AD和相关痴呆症的病因（ADRD）。