Role of the CX3CL1 C-terminus in reversing age-dependent Alzheimers neurodegeneration

摘要 阿尔茨海默病（AD）是最常见的年龄依赖性神经退行性疾病。神经元如何 尽管许多研究假设有毒的 β-淀粉样肽在 AD 大脑中丢失，但仍然存在争议。 各种形式（例如可溶性多聚体或寡聚体）的 (Aβ) 以及 tau 聚集体有助于神经元 衰老的 AD 大脑丧失和 AD 患者的突触功能障碍。 PS19、5XFAD等AD鼠标型号 确实会发展出年龄依赖性神经发生，支持上述主张。目前，AD治疗主要集中在 开发药物来阻止或消除淀粉样蛋白沉积或 tau 蛋白聚集。在本提案中，我们的目标是 研究如何通过逆转AD大脑中的神经元损失作为替代治疗策略 退化过程。我们最近发现小鼠过度表达全长 CX3CL1 (Tg-CX3CL1) 或 CX3CL1 的 C 末端结构域 (Tg-CX3CL1-ct) 显示增强的神经发生。 CX3CL1，也称为 fractalkine，是一种 I 型跨膜趋化因子（Bazan 等，1997；Pan 等） al., 1997) 并被 ADAM10 (Hurst et al., 2012;Hundhausen et al., 2003) 切割以释放其 N 末端 含有 C-XXX-C 基序的片段，介导与 G 蛋白偶联 CX3CR1 受体的结合 (Imai 等人，1997）。自从CX3CL1被发现以来，其生物学功能已被独家证明发生 通过CX3CL1/CX3CR1相互作用，激活信号转导来调节炎症反应， 白细胞捕获和浸润，以及其他免疫功能。然而，我们发现，C- 末端结构域具有反向信号传导功能，可调节对细胞生长重要的基因的表达 或分化。我们的目的是检验 CX3CL1 的神经元表达增强的假设 通过其 C 末端结构域促进神经发生，补充神经元损失并促进神经元的恢复 AD 小鼠模型中的突触功能。提出了三个具体目标来检验这一假设： 目标 1： 确定 CX3CL1 C 末端结构域 (CX3CL1-ct) 在控制神经发生中的作用；目标 2：增强 神经发生逆转 AD 小鼠模型中受损的突触功能；目标 3：探索潜力 CX3CL1-ct 在 AD 治疗的年龄依赖性神经发生中的治疗用途。完成实验 所提出的将为 CX3CL1 在 AD 治疗中的转化潜力提供新的答案。知识 这项研究的成果将指导未来 AD 组合疗法分子的开发 不仅可以减少淀粉样蛋白沉积或 tau 蛋白聚集，还可以补充神经元。

ABSTRACT Alzheimer's disease (AD) is the most common age-dependent neurodegenerative disease. How neurons are lost in AD brains remains contested, although many studies have postulated that toxic β-amyloid peptide (Aβ) in various forms (such as soluble multimers or oligomers) as well as tau aggregates contribute to neuronal loss in aging AD brains and synaptic dysfunction in AD patients. AD mouse models such as PS19 and 5XFAD do develop age-dependent neurogeneration, supporting the above assertion. Currently, AD therapy is centered on developing drugs to block or remove amyloid deposition or tau aggregation. In this proposal, we aim to investigate how to revert neuronal loss in AD brains as an alternative therapeutic strategy by reversing degenerative processes. We have recently discovered that mice overexpressing either full-length CX3CL1 (Tg-CX3CL1) or the C-terminal domain of CX3CL1 (Tg-CX3CL1-ct) show enhanced neurogenesis. CX3CL1, which is also known as fractalkine, is a type I transmembrane chemokine (Bazan et al., 1997;Pan et al., 1997) and is cleaved by ADAM10 (Hurst et al., 2012;Hundhausen et al., 2003) to release its N-terminal fragment containing the C-XXX-C motif, which mediates binding to the G protein-coupled CX3CR1 receptor (Imai et al., 1997). Since the discovery of CX3CL1, its biological functions have exclusively been shown to occur through CX3CL1/CX3CR1 interactions, which activate signal transduction to regulate inflammatory responses, leukocyte capture and infiltration, as well as other immune functions. However, we have discovered that the C- terminal domain has a back-signaling function, which regulates the expression of genes important for cell growth or differentiation. We aim to test the hypothesis that neuronal expression of CX3CL1 enhances neurogenesis through its C-terminal domain, which replenishes neuronal loss and fosters recovery of synaptic functions in AD mouse models. Three specific aims are proposed to test this hypothesis: Aim 1: To determine the role of CX3CL1 C-terminal domain (CX3CL1-ct) in the control of neurogenesis; Aim 2: To enhance neurogenesis to reverse impaired synaptic functions in AD mouse models; and Aim 3: To explore potential therapeutic use of CX3CL1-ct in age-dependent neurogenesis for AD therapy. Accomplishing the experiments as proposed will provide novel answers as to the translational potential of CX3CL1 in AD treatment. Knowledge gained from this study will guide future development of molecules targeted as an AD combinatorial therapy that will not only reducing amyloid deposition or tau aggregation, but will also replenish neurons.