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

项目概要 在体内平衡和适当的急性免疫反应期间，白细胞介素 18 (IL-18) 充当更高水平的促进剂 大脑功能并作为警报分子向细胞发出即将到来的危险信号。我们的研究使我们发现 IL-18 通路中的内源性反调节成分在阿尔茨海默病 (AD) 中受损， 这会导致过度且长时间的信号传导。更重要的是，我们发现了令人信服的证据 该过程在 tau 蛋白的失调及其病理物种的积累中发挥着重要作用。调查中 IL-18 通路受 AD 影响并驱动 tau 病理的潜在机制可能： 因此，需要找到新的方法来减轻这种潜在的疾病。在这里，我们提出了三个目标来调查这一问题 重要问题。在目标 1 中，我们假设 β-淀粉样蛋白 (Aβ) 会破坏内吞蛋白 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 在神经元细胞培养物和 AD 小鼠模型中，Tollip 的基因上调或下调。结果 这一目标可能表明，神经元中慢性 IL-18 信号传导诱导的 tau 病理形式的积累是， 至少部分是由于 IL-18R 运输和降解受损而上调所致 由托利普调解。对于第二个目标，我们将检验以下假设：IL-产生不足 18 的内源性诱饵受体 IL-18 结合蛋白 (IL-18BP) 也在慢性激活 AD中的这条途径。我们将使用腺相关病毒来上调 AD 小鼠中的 IL-18BP 水平 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物化学和蛋白质组学 绘制受 IL-18 影响的神经元细胞内网络的方法。我们将应用药理 以及将 IL-18 改变的潜在候选物（例如蛋白激酶和磷酸酶）与 tau 蛋白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 级联反应可以让我们找到新的策略来抑制 IL-18 的病理作用，同时保留 其相关的生理功能。总体而言，我们的研究具有重要意义，原因有二：首先，它们将提供 对 IL-18 信号级联有更深入的了解，其次，他们将具体揭示关键步骤 参与 AD 中的 IL-18 通路，并可能导致新的候选治疗药物的鉴定 有可能将我们的发现转化为临床。

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.