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).

项目概要/摘要阿尔茨海默氏病 (AD) 对全球人口老龄化产生重大影响，包括细胞和机体炎症。水平，通常伴随着衰老过程；而在散发性 AD 中，神经炎症越来越受到重视。然而，神经炎症反应的分子触发因素和介导因素基于核酸的抗病毒防御机制的调控仍然是个谜。寄生虫，尤其是入侵病毒，I 型干扰素 (IFN) 细胞因子是先天抗病毒的关键成分。免疫，是检测病毒的哺乳动物核酸先天免疫传感器信号激活的产物我们最近报道斑块相关的小胶质细胞对基因组或其复制产物有先天反应。含有核酸的β淀粉样蛋白（Aβ）斑块并促进各种Aβ的慢性神经胶质增生和突触损失尽管在临床 AD 模型中 IFN 通路显着上调，但 IFN 通路却随着 BRAAK 的增加而意外升高。分期，这意味着与人类 tau 病理学相关的特殊 IFN 反应。证实了不同小鼠 tau 病模型中显着的 IFN 通路激活是一个核心。衰老细胞的表观基因组失调并抑制转座因子（TE 或转座子），内源性寄生虫广泛分布在基因组中，激活L1。逆转录转座元件触发抗病毒先天免疫反应，从而产生干扰素。我们发现 tau 过度表达会松弛神经异染色质，这与升高相关值得注意的是，IFN 信号在衰老的大脑中被激活。多个 ISG 的多态性作为一个群体强加为 AD 的危险因素。我们试图研究 AD 期间抗病毒免疫反应如何与去抑制的转座子活性相结合具体而言，我们计划检查 L1 和逆转录因子在发病机制中的参与。结合 tau 蛋白病和衰老条件下神经炎症的发作（目标 1），确定关键信号传导介质促进大脑中 tau 刺激的抗病毒反应（目标 2）并阐明表观遗传对 tau 蛋白病和脑衰老中转座子去抑制和抗病毒炎症的影响（目标 3）。