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) 的特点是斑块和β淀粉样蛋白 (Aβ) 的积累神经原纤维缠结中的 tau 蛋白过度磷酸化，以及神经血管功能障碍和神经炎症，临床和临床前研究均表明，它们共同导致神经退行性变和认知障碍。表明神经炎症，特别是异常和慢性小胶质细胞激活，是 AD 的一个主要部分病因学。先天免疫是宿主抵御病原体和有害物质入侵的第一道防线。进化由保守的模式识别受体组成，包括细胞表面的 Toll 样受体和细胞内囊泡，以及核苷酸传感器，例如用于胞质 DNA 的环 GMP-AMP 合酶 (cGAS)。这些先天信号通路的激活会触发炎症细胞因子的产生和干扰素，并通过激活大量干扰素刺激基因进一步放大免疫反应。这表明，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 发病机制的贡献仍然存在尚未充分探索。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基础神经炎症的机制，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 发生和进展的关键生物学过程。初步研究表明，AD 死后大脑样本中胞质 dsDNA 水平增加，并且 5xFAD 小鼠模型，与 cGAS-STING 通路激活密切相关，更重要的是，与 cGAS 通路激活密切相关。敲除小鼠改善了 5xFAD 模型中的神经炎症和淀粉样蛋白病理，这可能是为了更好地了解 AD 中的 cGAS-STING 通路，模拟了 STING 抑制剂 H-151 的治疗。我们现在建议研究：1）使用三细胞体外神经炎症的 cGAS-STING 依赖性调节 iPSC 衍生细胞培养系统，以及 cGAS 和 STING 抑制动物模型中的 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，包括大脑和脉络丛类器官，在信号传导和转录组水平；3) HSV1 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，我们希望能够深入了解cGAS-STING先天免疫中枢神经系统感染、炎症和 AD 发病机制中的通路，并为感染性疾病提供新的见解 AD 和相关痴呆 (ADRD) 的病因学。