Antiviral response coupled with transposon derepression in Alzheimer's disease and aging

抗病毒反应与转座子去抑制在阿尔茨海默病和衰老中的作用

基本信息

批准号：
10629440
负责人：
Wei Cao
金额：
$ 64.75万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629440
关键词：
Achievement Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Antiviral Response Biogenesis Brain Brain Mapping Brain region Cells Central Nervous System Chronic Clinic Coupled DNA Transposable Elements Defense Mechanisms Elements Encephalitis Epigenetic Process Event Genetic Polymorphism Genetic Transcription Genome Genomic Instability Genomics Gliosis Goals Heterochromatin Human Immune Immune response Immune signaling In Vitro Inflammaging Inflammation Innate Immune Response Interferons Invaded Kinetics Late Onset Alzheimer Disease Mediating Mediator Methylation Microglia Modeling Modification Molecular Mus Natural Immunity Nerve Degeneration Neuroglia Neurons Nucleic Acids Outcome Parasites Pathogenesis Pathology Pathway interactions Phenotype Play Population Process Production Reaction Relaxation Reporter Reporting Retroelements Retrotransposition Role Senile Plaques Signal Transduction Staging Sting Injury Synapses Tauopathies Testing Therapeutic Intervention Viral Viral Genome Virus aged aging brain brain cell cell type cohort cytokine derepression epigenome in vivo in vivo Model innate immune pathways insight molecular targeted therapies neuroinflammation novel overexpression phenotypic biomarker response senescence sensor tau Proteins transgene expression viral detection

项目摘要

Project Summary/Abstract Alzheimer's disease (AD) significantly impacts aging populations worldwide. Inflammation, at cell and organismic levels, often accompanies aging process; whereas in sporadic AD, neuroinflammation is increasingly recognized as a major contributor. However, the molecular triggers for neuroinflammatory response and factors mediating and regulating the process remains enigmatic. Antiviral defense mechanisms control nucleic acid-based parasites, most noticeably the invading viruses. Type I IFN (IFN) cytokines, a key component of antiviral innate immunity, is a product of signaling activation of mammalian nucleic acid innate immune sensors that detect viral genomes or their replication products. We recently reported that plaque-associated microglia innately reacted to nucleic acid-containing amyloid β (Aβ) plaques and promote chronic gliosis and synapse loss in various Aβ models. While grossly upregulated in clinic AD, IFN pathway unexpectedly escalates with increased BRAAK staging, which implies an idiosyncratic IFN response in association with human tau pathology. We have since confirmed a prominent IFN pathway activation in different murine tauopathy models. Genomic instability is a core hallmark of aging. Senescent cells dysregulate their epigenome and derepress transposable elements (TE or transposons), endogenous parasites widely distributed in the genome. Consequently, activation of L1 retrotransposable element triggers an antiviral innate immune response, resulting in IFN production. In parallel, we found that tau overexpression relaxed neuronal heterochromatin, which is correlated with elevated transcription of L1 and other TEs in tauopathy brains. Remarkably, IFN signaling is activated in aging brain and polymorphisms of several ISGs as a group impose as a risk factor for AD. Based on these intriguing findings, we seek to investigate how antiviral immune response is coupled to derepressed transposon activity during AD pathogenesis in this proposal. Specifically, we plan to examine the involvement of L1 and retroelements in conjunction with the onset of neuroinflammation under tauopathy and aging conditions (aim 1), identify the key signaling mediators facilitating tau-stimulated antiviral response in the brain (aim 2) and elucidate epigenetic influence on transposon derepression and antiviral inflammation in tauopathy and brain aging (aim 3).

项目摘要/摘要阿尔茨海默氏病（AD）显着影响全球衰老的人口。炎症，细胞和生物体水平，通常涉及衰老过程；而在零星的AD中，神经炎症越来越多地认识到作为主要贡献者。但是，分子触发神经炎症反应和介导的因素控制过程仍然神秘。抗病毒防御机制控制基于核酸的寄生虫，最明显的是入侵病毒。 I型IFN（IFN）细胞因子，这是抗病毒先天的关键组成部分免疫力是哺乳动物核酸先天免疫传感器的信号激活的产物，该传感器检测病毒基因组或其复制产物。我们最近报道说，与菌斑相关的小胶质细胞天生反应含核酸的淀粉样蛋白β（Aβ）斑块，并促进各种Aβ的慢性神经胶质和突触丧失型号。虽然在诊所广告中严重更新，但IFN途径意外地随着Braak的增加而升级分期，这意味着与人类tau病理相关的特质IFN反应。从那以后我们就有了在不同的鼠Tauopathy模型中确认了突出的IFN途径激活。基因组不稳定性是核心衰老的标志。衰老细胞失调其表观基因组和除外的转座元件（TE或转座子），内源性寄生虫广泛分布在基因组中。因此，激活L1 逆转录元件触发了抗病毒先天免疫反应，从而导致IFN产生。并联，我们发现Tau过表达松弛的神经元异染色质与升高有关 tauopathy大脑中L1和其他TE的转录。值得注意的是，IFN信号传导在衰老的大脑中被激活几个ISG作为一个组的多态性将其作为AD的危险因素。基于这些有趣的发现，我们试图研究抗病毒免疫响应如何与AD期间的抗压力转座子活性耦合该提案中的发病机理。具体而言，我们计划检查L1和重新元素的参与与tauopathy和衰老状况下神经炎症的发作有关（AIM 1），确定钥匙信号传导介质支持大脑中TAU刺激的抗病毒反应（AIM 2）并阐明表观遗传对tauopathy和大脑衰老的转座子消性和抗病毒感染的影响（AIM 3）。