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

项目总结/摘要 阿尔茨海默病（AD）严重影响全球老龄化人口。细胞和器官炎症 水平，通常伴随着衰老过程;而在散发性AD中，神经炎症越来越多地被认识到， 作为主要贡献者。然而，神经炎症反应的分子触发因子和介导因子 调控这一过程仍然是个谜。抗病毒防御机制控制核酸为基础的 寄生虫，最明显的是入侵病毒。I型干扰素（IFN）细胞因子，抗病毒先天性 免疫，是哺乳动物核酸先天免疫传感器的信号传导激活的产物， 基因组或其复制产物。我们最近报道，斑块相关的小胶质细胞天生对 含核酸的淀粉样蛋白β（Aβ）斑块，并促进各种Aβ中的慢性胶质增生和突触丢失。 模型虽然在临床AD中显著上调，但IFN途径意外地随着BRAAK增加而升级。 分期，这意味着与人tau病理学相关的特异质IFN应答。我们已经 证实了在不同的鼠tau蛋白病模型中显著的IFN途径活化。基因组的不稳定性是 衰老的标志衰老细胞失调其表观基因组和解抑制转座因子（TE或 转座子），广泛分布在基因组中的内源性寄生虫。因此，L1的激活 逆转录转座因子触发抗病毒先天免疫应答，导致IFN产生。同时， 我们发现，tau蛋白过度表达使神经元异染色质松弛，这与神经元异染色质水平升高有关。 Tau病大脑中L1和其他TE的转录。值得注意的是，IFN信号在衰老的大脑中被激活， 作为一个组的几个ISG的多态性作为AD的危险因素强加。基于这些有趣的发现， 我们试图研究AD期间抗病毒免疫应答如何与去抑制的转座子活性偶联， 在这个提案中，具体来说，我们计划研究L1和retroelements的参与， 结合tau蛋白病和衰老条件下神经炎症的发作（目的1），确定关键 促进大脑中tau刺激的抗病毒反应的信号传导介质（aim 2），并阐明表观遗传 对tau蛋白病和脑老化中转座子去阻遏和抗病毒炎症的影响（目的3）。

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).