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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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氏病（AD）中进行了更新，被认为可以推动广告发病。 AD中不良适应性抗病毒反应的特定介体仍不清楚。先天免疫系统利用一系列核酸传感器检测病毒遗传物质激活干扰素表达。细胞中的中央DNA传感器是环状GMP-AMP合酶（CGA）。 CGAS信号具有在许多神经退行性疾病等许多神经退行性疾病中成为重要参与者侧硬化。 CGA信号在TAU介导的神经退行性中的作用仍然没有研究。我们发现 CGAS信号在表达突变体Tau（P301S小鼠）和人AD的小鼠的大脑中过度活化患者。使用行为测定，电生理读数和单核RNA测序，我们初步结果表明，CGAS活性会修饰细胞对和功能性缺陷的反应由tauopathy引起。我们观察到CGA的部分或完全丢失检索了Tauopathy相关的空间学习和记忆定义。 CGA在包括小胶质细胞在内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应激并显示 CGA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降低疾病小胶质细胞中的基因。尚不清楚tau如何改变线粒体和核动力学以激活 CGA以及CGA激活如何增强TAU的神经毒性作用。该提议将调查 CGA和核酸传感途径的机制和后果。我的目标是剖析 CGAS激活的分子机制响应TAU，通过关注TAU依赖性细胞过程诱导线粒体应力和小胶质细胞感应（AIM 1），并研究CGAS培养物如何调子疗法中的不良适应性小胶质细胞反应和神经元损伤（AIM 2）。最后，由于抗病毒反应可能是特定于特定的，有很强的理由将小鼠先天核酸敏感性的研究扩展到人类模型。人和小鼠CGA仅具有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）的平台来研究更广泛的核酸传感途径并执行公正的CRISPR屏幕，以识别人类核酸的新调节剂感测tau毒性（目标3）。该提案中概述的实验将导致更好地理解核酸传感器在tauopathy和AD中的作用可能被证明是人类。