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

项目概要/摘要 阿尔茨海默病 (AD) 严重影响全球人口老龄化。细胞和有机体的炎症 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 作为主要贡献者。然而，神经炎症反应的分子触发因素和介导因素 对该过程的监管仍然是个谜。抗病毒防御机制控制基于核酸 寄生虫，最明显的是入侵的病毒。 I 型干扰素 (IFN) 细胞因子是天然抗病毒药物的关键成分 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 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对 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 模型。虽然在临床 AD 中显着上调，但 IFN 通路随着 BRAAK 的增加而意外升级 分期，这意味着与人类 tau 病理学相关的特殊 IFN 反应。我们从那时起 证实了不同小鼠 tau 病模型中显着的 IFN 通路激活。基因组不稳定性是核心 衰老的标志。衰老细胞的表观基因组失调并抑制转座元件（TE 或 转座子），内源性寄生虫广泛分布在基因组中。因此，L1 的激活 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。同时， 我们发现 tau 过度表达会松弛神经元异染色质，这与升高相关 L1 和其他 TE 在 tau 蛋白病变大脑中的转录。值得注意的是，干扰素信号在衰老的大脑中被激活，并且 多个 ISG 的多态性作为一个群体强加为 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如何与去抑制的转座子活性相结合 本建议中的发病机制。具体来说，我们计划检查 L1 和逆转录因子在 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）。

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).