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

项目摘要/摘要 阿尔茨海默病(AD)严重影响全球老龄化人口。炎症，在细胞和组织中 水平，通常伴随着衰老过程；而在散发性AD中，神经炎症越来越被认识到 作为主要贡献者。然而，神经炎性反应的分子触发因素和中介因子 监管这一过程仍然是个谜。抗病毒防御机制控制基于核酸的 寄生虫，最引人注目的是入侵的病毒。I型干扰素细胞因子，先天抗病毒的关键成分 免疫，是哺乳动物检测病毒的核酸天然免疫传感器信号激活的产物 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先天对 核酸淀粉样蛋白β(A-β)斑块与各种A-β的慢性胶质增生和突触丢失 模特们。虽然在临床AD中大量上调，但随着Braak的增加，干扰素途径意外地升级 分期，这意味着与人类tau病理相关的特殊的干扰素反应。从那以后我们就 证实在不同的小鼠共济失调模型中有显著的干扰素途径激活。基因组不稳定性是一个核心 这是衰老的标志。衰老细胞失调其表观基因组，并降低转座元件(TE或 转座子)，内生寄生虫广泛分布在基因组中。因此，L1的激活 逆转录转座元件可触发抗病毒的先天免疫反应，导致干扰素的产生。同时， 我们发现，tau的过度表达松弛了神经元异染色质，这与升高的 脊椎病患者脑内L1和其他TES的转录。值得注意的是，干扰素信号在老化的大脑和 作为一个群体，几个ISG基因的多态性是AD的危险因素。基于这些有趣的发现， 我们试图研究AD期间抗病毒免疫反应与去抑制转座子活性之间的关系 发病机制在这一建议中。具体地说，我们计划研究L1和逆转录因子在 结合肌萎缩侧索硬化症和衰老条件下的神经炎症发作(目标1)，找出关键 促进tau刺激的脑内抗病毒反应的信号介质(Aim 2)和阐明表观遗传学 转座子去抑制和抗病毒炎症在紧张症和脑老化中的影响(目标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).