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.

项目摘要 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AD的驱动因素 发病机制AD中适应不良抗病毒反应的特异性介质仍不清楚。先天 免疫系统利用一系列核酸传感器来检测病毒遗传物质以激活干扰素 表情细胞中的中心DNA传感器是环GMP-AMP合酶（cGAS）。CGAS信号传导具有 在许多神经退行性疾病如帕金森病和肌萎缩性神经病中起着重要作用。 侧索硬化cGAS信号在tau介导的神经变性中的作用尚未研究。我们发现 cGAS信号在表达突变tau的小鼠（P301 S小鼠）和人AD的大脑中被过度激活， 患者使用行为分析，电生理读数和单核RNA测序，我们 初步结果表明，cGAS活性改变了细胞的反应和功能缺陷， 是由tau蛋白病引起的我们观察到Cgas的部分或完全丧失挽救了tau蛋白病相关的空间表达。 学习和记忆缺陷。CGAS在包括小胶质细胞的免疫细胞中高度富集。我们发现tau 通过触发小胶质细胞中的线粒体DNA应激诱导cGAS依赖性干扰素特征， Cgas缺失改变了小胶质细胞疾病的转化，其特征是干扰素的表达减少， 疾病小胶质细胞中的基因。目前尚不清楚tau蛋白如何改变线粒体和核动力学， cGAS以及cGAS激活如何增强tau的神经毒性作用。该提案将调查 tau蛋白病中cGAS和核酸传感途径的机制和后果。我的目标是剖析 通过聚焦于tau依赖性细胞过程，cGAS激活响应于tau的分子机制 诱导线粒体应激和小胶质细胞衰老（目的1），并研究cGAS如何介导 tau蛋白病中的适应不良小胶质细胞反应和神经元损伤（目的2）。最后，由于抗病毒反应 可能是物种特异性的，有很强的理由将先天核酸传感的小鼠研究扩展到 人体模型人和小鼠cGAS仅共享60%的氨基酸相似性，并且具有不同的激活 要求.我将建立基于人类多能干细胞（hPSC）的平台，以研究更广泛的核酸 传感途径，并进行无偏CRISPR筛选，以识别人类核酸的新型调节剂 在tau毒性中感测（Aim 3）。本提案中概述的实验将有助于更好地理解 核酸传感器在tau蛋白病和AD中的作用，这可能被证明可以翻译到人类。