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

CX3CL1 C 末端在逆转年龄依赖性阿尔茨海默病神经变性中的作用

基本信息

批准号：
9691661
负责人：
RIQIANG YAN
金额：
$ 277.67万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9691661
关键词：
Role CX3CL1 terminus reversing age

项目摘要

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.

抽象的阿尔茨海默病（AD）是最常见的年龄依赖性神经退行性疾病。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。各种形式的 (Aβ)（例如可溶性多聚体或寡聚体）以及 tau 聚集体有助于神经元 AD 小鼠模型（如 PS19 和 5XFAD）中衰老的 AD 大脑丧失和突触功能障碍。确实会发展出年龄依赖性神经发生，支持了上述论点。目前，AD 治疗处于中心地位。关于开发药物来阻止或消除淀粉样蛋白沉积或 tau 蛋白聚集在这项提案中，我们的目标是研究如何通过逆转 AD 大脑的神经损失作为替代治疗策略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 et al., 1997;Pan et al., 2017)。 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，它的生物学功能已被完全证实。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，但是，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我们的目的是检验 CX3CL1 的神经表达增强的假设。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。所提出的将为 CX3CL1 在 AD 治疗中的转化潜力提供新的答案。这项研究获得的成果将指导未来 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。