Deciphering the role of interleukin-18 as a driver of tau pathology in Alzheimer's disease

项目总结 在动态平衡和适当的急性免疫反应中，白细胞介素18(IL-18)起促进剂的作用 大脑功能，并作为警报分子，向细胞发出危险到来的信号。我们的研究使我们发现 在阿尔茨海默病(AD)中受损的IL-18途径中的内源性反调节成分， 这会导致过度和长时间的信号传递。更重要的是，我们发现了令人信服的证据 过程在tau的失调和其病理性物种的积累中起着重要作用。调查 IL-18途径在AD中受tau病理的影响和驱动的潜在机制可能是， 因此，产生新的方法来减轻这种潜伏的疾病。在这里，我们提出了三个目标来调查这一点 重要的问题。在目标1中，我们假设β-淀粉样蛋白(Aβ)破坏内吞蛋白Tollip(Toll相互作用 蛋白)，它是驱动IL-18受体(IL-18R)同源脱敏的主要调节因子。我们 将在神经细胞培养和AD小鼠模型中从基因上上调或下调Tollip的表达。其结果是 这一目的可能表明，慢性IL-18信号在神经元中诱导的tau病理形式的积聚， 至少部分原因是由于IL-18R的贩运和降解受到损害而导致其上调 由托利普调停。对于第二个目标，我们将检验这样的假设，即产生IL-1的缺陷 18‘S内源性诱骗受体IL-18结合蛋白(IL-18BP)也在慢性活化中发挥作用。 AD中的这一途径。我们将使用腺相关病毒上调AD小鼠和 确定其对AD样病理的治疗效果。最后，我们的最后一个目标是利用生化和蛋白质组学 方法绘制受IL-18影响的神经元细胞内网络图。我们将应用药理作用 以及基因工具，将IL-18改变的潜在候选基因，如蛋白激酶和磷酸酶，与 Tau蛋白的过度磷酸化以及随后的突触丧失和认知能力下降。建立这些细胞内的 级联反应可以让我们确定新的策略来抑制IL-18的病理影响，同时保持 其相关的生理功能。总体而言，我们的研究具有重要意义，原因有两个：第一，它们将提供 对IL-18信号级联的更深入的洞察，第二，他们将具体揭示关键步骤 参与了阿尔茨海默病的IL-18途径，并可能导致新的候选治疗方法的确定 有可能将我们的发现转化为临床应用。

PROJECT SUMMARY During homeostasis and proper acute immune responses, interleukin-18 (IL-18) acts as a facilitator of higher cerebral functions and as an alarmin molecule to signal incoming danger to cells. Our studies led us to discover endogenous counter-regulatory components in the IL-18 pathway that are impaired in Alzheimer's disease (AD), which results in excessive and prolonged signaling. More importantly, we found compelling evidence that this process plays a major role in the dysregulation of tau and accumulation of its pathological species. Investigating the underlying mechanisms by which the IL-18 pathway is affected by and drives tau pathology in AD could, therefore, yield novel means to mitigate this insidious disease. Here we propose three aims to investigate this important issue. In aim 1, we hypothesize that β-amyloid (Aβ) disrupts the endocytic protein Tollip (toll interacting protein), which is the leading regulator driving the homologous desensitization of the IL-18 receptor (IL-18R). We will genetically up- or downregulate Tollip in neuronal cell cultures and in an AD mouse model. The outcome of this aim may show that the buildup of pathological forms of tau induced by chronic IL-18 signaling in neurons is, at least in part, caused by the upregulation of IL-18R due to the impairment of its trafficking and degradation mediated by Tollip. For the second aim, we will test the hypothesis that the deficiency in the production of IL- 18's endogenous decoy receptor, IL-18 binding protein (IL-18BP), also plays a role in the chronic activation of this pathway in AD. We will use an adeno associated virus to upregulate IL-18BP levels in AD mice and determine its therapeutic efficacy on AD-like pathology. Finally, our last aim utilizes biochemical and proteomic methods to map the neuronal intracellular networks affected in response to IL-18. We will apply pharmacological and genetic tools to link potential candidates altered by IL-18, such as protein kinases and phosphatases, to the hyperphosphorylation of tau and subsequent synaptic loss and cognitive decline. Establishing these intracellular cascades could allow us to identify novel strategies to inhibit the pathological effects of IL-18, while preserving its relevant physiological functions. Overall, our studies are significant for two reasons: first, they will provide greater insights into the IL-18 signaling cascade and second, they will uncover the critical steps specifically involved in the IL-18 pathway in AD, and may result in the identification of new therapeutic candidates to potentially translate our discoveries into the clinic.