Investigating the role of cGAS signaling and microglial senscence in tauopathy

研究 cGAS 信号传导和小胶质细胞感知在 tau 蛋白病中的作用

• 批准号: 10740642
• 负责人: Sadaf Amin
• 金额: $ 12.54万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-05 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740642
• 关键词: Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Amino Acids; Amyotrophic Lateral Sclerosis; Antiviral Response; Astrocytes; Behavioral Assay; Binding; Brain; CRISPR screen; Cell Culture Techniques; Cell physiology; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Cyclic GMP; Cytoplasm; Cytosol; DNA; DNA Damage; DNA Probes; Data; Dementia; Development; Disease; Electrophysiology (science); Exposure to; Extracellular Space; Genes; Genetic; Genetic Materials; Genomic Instability; Gliosis; Hippocampus; Human; Immune; Immune response; Immune signaling; Immunohistochemistry; In Vitro; Inflammaging; Inflammatory Response; Innate Immune Response; Innate Immune System; Interferon Activation; Interferons; Knowledge; Learning; Libraries; Mediating; Mediator; Memory Loss; Memory impairment; Microglia; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear; Nucleic Acids; Parkinson Disease; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Phase; Phenocopy; Public Health; RNA; Role; Senile Plaques; Series; Signal Transduction; Stimulator of Interferon Genes; Stress; Synapses; Synaptic plasticity; System; Tauopathies; Time; Toxic effect; Viral; Work; antiviral immunity; brain cell; efficacious treatment; experimental study; genome wide association study; human disease; human model; human pluripotent stem cell; hyperphosphorylated tau; immune activation; mitochondrial dysfunction; mouse model; neuroinflammation; neurotoxic; neurotoxicity; novel; protective effect; response; risk variant; screening; senescence; sensor; single nucleus RNA-sequencing; synaptic pruning; tau Proteins; tau aggregation; tau mutation; transcriptomics; viral detection

PROJECT SUMMARY Innate immune antiviral pathways are upregulated in Alzheimer’s disease (AD) and are thought to drive AD pathogenesis. The specific mediators of maladaptive antiviral responses in AD are still not understood. Innate immune system utilizes a series of nucleic acid sensors to detect viral genetic material to activate interferon expression. The central DNA sensor in the cell is cyclic GMP-AMP synthase (cGAS). cGAS signaling has emerged as an important player in many neurodegenerative diseases like Parkinson’s disease and amyotrophic lateral sclerosis. The role of cGAS signaling in tau-mediated neurodegeneration remains unstudied. We discover that cGAS signaling is hyperactivated in the brains of mice expressing mutant tau (P301S mice) and human AD patients. Using behavioral assays, electrophysiological readings and single nuclei RNA sequencing, our preliminary results indicate that cGAS activity modifies both the cellular responses to and the functional deficits caused by tauopathy. We observed that partial or complete loss of Cgas rescued tauopathy-associated spatial learning and memory deficits. cGAS is highly enriched in immune cells including microglia. We find that tau induces a cGAS-dependent interferon signature by triggering mitochondrial DNA stress in microglia and show that Cgas deletion alters microglial disease transformation, characterized by reduced expression of interferon genes in disease microglia. It is not known how tau can alter mitochondrial and nuclear dynamics to activate cGAS and how cGAS activation enhances neurotoxic effects of tau. This proposal will investigate the mechanisms and consequences of cGAS and nucleic acid sensing pathways in tauopathy. I aim to dissect the molecular mechanism of cGAS activation in response to tau by focusing on tau dependent cellular processes that induce mitochondrial stress and microglial senescence (Aim 1) and investigate how cGAS mediates maladaptive microglial responses and neuronal damage in tauopathy (Aim 2). Finally, since antiviral responses could be species-specific, there is strong rationale to extend mouse studies of innate nucleic acid sensing to human models. Human and mouse cGAS share only 60% amino acid similarity and have different activation requirements. I will establish human pluripotent stem cell (hPSC)-based platforms to study broader nucleic acid sensing pathways and perform unbiased CRISPR-screens to identify novel regulators of human nucleic acid sensing in tau toxicity (Aim 3). The experiments outlined in this proposal will lead to a better understanding of the role of nucleic acid sensors in tauopathy and AD which might prove translatable to humans.

项目总结 先天免疫抗病毒途径在阿尔茨海默病(AD)中上调，并被认为是导致AD的原因 发病机制。AD中不适应抗病毒反应的特定介体仍不清楚。先天的 免疫系统利用一系列核酸传感器检测病毒遗传物质以激活干扰素 表情。细胞内的中心DNA传感器是环状GMP-AMP合成酶(CGAS)。CGAS信令具有 成为许多神经退行性疾病的重要参与者，如帕金森氏病和肌营养不良 侧索硬化症。CGAS信号在tau介导的神经退行性变中的作用尚不清楚。我们发现 CGAS信号在表达突变型tau基因的小鼠(P301S小鼠)和人类AD中被过度激活 病人。使用行为分析、电生理读数和单核RNA测序，我们的 初步结果表明，cGAS活性改变了细胞对功能缺陷的反应 由紧张症引起的。我们观察到，cGAS的部分或全部丧失挽救了与颈椎病相关的空间 学习和记忆缺陷。CGAS高度富含免疫细胞，包括小胶质细胞。我们发现了牛头 通过触发小胶质细胞线粒体DNA应激诱导cGAS依赖的干扰素信号，并显示 CGAS缺失改变了以干扰素表达减少为特征的小胶质细胞疾病转化 疾病小胶质细胞中的基因。目前尚不清楚tau如何改变线粒体和核的动力学以激活 CGAS以及cGAS激活如何增强tau的神经毒性效应。这项提案将调查 肌萎缩侧索硬化症中cGAS和核酸传感通路的机制和后果。我的目标是剖析 CGAS激活反应tau依赖的细胞过程的分子机制 诱导线粒体应激和小胶质细胞衰老(Aim 1)，并研究cGAS如何介导 肌萎缩侧索硬化症患者的适应不良小胶质细胞反应和神经元损伤(目标2)。最后，由于抗病毒反应 可能是特定物种的，有很强的理由将小鼠天生核酸感应的研究扩展到 人体模型。人和小鼠cGAs的氨基酸相似性只有60%，具有不同的活性 要求。我将建立基于人类多能干细胞(HPSC)的平台来研究更广泛的核酸 感知途径和进行无偏CRISPR筛选以识别人类核酸的新调控因子 检测tau毒性(目标3)。这项提案中概述的实验将有助于更好地理解 核酸传感器在变态反应和AD中的作用，这可能被证明是人类可以翻译的。