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

项目摘要 在体内平衡和适当的急性免疫应答过程中，白细胞介素-18（IL-18）作为一种促进剂， 大脑功能，并作为警报分子向细胞发出危险信号。我们的研究发现 在阿尔茨海默病（AD）中受损的IL-18途径中的内源性反调节组分， 这导致过度和延长的信号传导。更重要的是，我们发现了令人信服的证据， 该过程在tau的失调和其病理种类的积累中起主要作用。调查 IL-18途径受AD中tau病理学影响并驱动该病理学的潜在机制可能， 因此，产生新的手段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。在目的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），其是驱动IL-18受体（IL-18 R）同源脱敏的主要调节剂。我们 将在神经元细胞培养物和AD小鼠模型中遗传上调或下调Tollip。的结果 该目的可以表明神经元中由慢性IL-18信号传导诱导的病理形式的tau的积累， 至少部分是由于IL-18 R的运输和降解受损而导致的IL-18 R的上调引起的 由Tollip调解。对于第二个目标，我们将测试的假设，即在生产的IL- 18的内源性诱饵受体，IL-18结合蛋白（IL-18 BP），也在慢性激活中起作用。 AD中的这条通路。我们将使用腺相关病毒来上调AD小鼠中的IL-18 BP水平， 确定其对AD样病理的治疗功效。最后，我们的最后一个目标是利用生物化学和蛋白质组学 绘制响应IL-18而受影响的神经元细胞内网络的方法。我们将应用药理学 和遗传工具，将IL-18改变的潜在候选物（例如蛋白激酶和磷酸酶）与 tau过度磷酸化和随后的突触丧失和认知下降。建立这些细胞内 级联反应可以使我们确定新的策略，以抑制IL-18的病理作用，同时保留 相关的生理功能。总的来说，我们的研究是重要的，原因有两个：第一，他们将提供 更深入地了解IL-18信号级联，其次，他们将揭示关键步骤，特别是 参与AD的IL-18通路，并可能导致识别新的治疗候选物， 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.