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.

项目概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 AD 中适应不良抗病毒反应的具体介导因素仍不清楚。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细胞中的中心 DNA 传感器是环 GMP-AMP 合酶 (cGAS)。成为许多神经退行性疾病（如帕金森病和肌萎缩症）的重要参与者我们发现，cGAS 信号在 tau 介导的神经变性中的作用尚未得到研究。 cGAS 信号在表达突变 tau 的小鼠（P301S 小鼠）和人类 AD 的大脑中过度激活我们使用行为分析、电生理读数和单核 RNA 测序来分析患者。初步结果表明，cGAS 活性可以改变细胞反应和功能缺陷我们观察到 Cgas 的部分或完全丧失挽救了 tau 蛋白病相关的空间。我们发现，cGAS 在包括小胶质细胞在内的免疫细胞中高度丰富。通过触发小胶质细胞中的线粒体 DNA 应激来诱导 cGAS 依赖性干扰素特征，并显示 Cgas 缺失改变了小胶质细胞疾病转化，其特征是干扰素表达减少目前尚不清楚 tau 蛋白如何改变线粒体和核动力学以激活。 cGAS 以及 cGAS 激活如何增强 tau 的神经毒性作用。我的目的是剖析 tau 蛋白病中 cGAS 和核酸传感途径的机制和后果。通过关注 tau 依赖性细胞过程，研究 cGAS 响应 tau 激活的分子机制诱导线粒体应激和小胶质细胞衰老（目标 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（目标 2）。可能是物种特异性的，因此有充分的理由将先天核酸传感的小鼠研究扩展到人类模型和小鼠 cGAS 仅具有 60% 的氨基酸相似性，并且具有不同的激活作用。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。传感途径并进行公正的 CRISPR 筛选，以确定人类核酸的新型调节因子感知 tau 毒性（目标 3）。核酸传感器在 tau 蛋白病和 AD 中的作用可能被证明可以应用于人类。