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

• 批准号: 9456462
• 负责人: RIQIANG YAN
• 金额: $ 10.87万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9456462
• 关键词: Address; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid deposition; Animal Testing; Back; Binding; Biochemical; Biological Assay; Biological Process; Bone Morphogenetic Proteins; Brain Diseases; Breeding; Bromodeoxyuridine; C-terminal; CX3CL1 gene; Cell Differentiation process; Cleaved cell; Coupled; Cultured Cells; Data; Development; Elderly; Electrophysiology (science); Elements; Event; Fostering; Fractalkine; Functional disorder; Future; G-substrate; GTP-Binding Proteins; Gene Expression; Gene Targeting; Generations; Genes; Goals; Impaired cognition; Impairment; Infiltration; Inflammatory Response; Knowledge; Label; Late Onset Alzheimer Disease; Length; Leukocytes; Longevity; Luciferases; Mediating; Membrane; Methods; Mus; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Patients; Peptide Signal Sequences; Peptides; Pharmaceutical Preparations; Prions; Process; Recovery; Regulation; Reporting; Role; Senile Plaques; Signal Transduction; Site; Synapses; Synaptic plasticity; Testing; Tetracycline Control; Tetracyclines; Therapeutic; Therapeutic Uses; Transforming Growth Factor beta; Transgenes; Transgenic Mice; Validation; adult neurogenesis; age related; aging brain; aging population; alpha secretase; behavior test; beta-site APP cleaving enzyme 1; cell growth; chemokine; cognitive function; combinatorial; experimental study; gamma secretase; immune function; improved; mature animal; mouse model; neuroblastoma cell; neurogenesis; neuron loss; novel; overexpression; polypeptide C; promoter; receptor; secretase; small molecule; subventricular zone; synaptic function; tau aggregation; tau mutation; transcriptome sequencing

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.

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。神经元是如何 尽管许多研究假设有毒的β-淀粉样多肽在AD大脑中丢失，但仍有争议 各种形式的(a-β)(如可溶性多聚体或寡聚体)以及tau聚集体对神经元有贡献 老年性阿尔茨海默病患者的脑老化和突触功能障碍。PS19和5XFAD等AD鼠标型号 确实发展了年龄依赖的神经生成，支持上述断言。目前，AD的治疗主要集中在 开发阻断或消除淀粉样蛋白沉积或tau聚集的药物。在这项建议中，我们的目标是 研究如何通过逆转逆转AD脑内神经元丢失作为替代治疗策略 退化过程。我们最近发现，小鼠过表达全长CX3CL1 (Tg-CX3CL1)或CX3CL1的C-末端结构域(Tg-CX3CL1-ct)显示神经发生增强。 CX3CL1，也被称为Fractalkine，是一种I型跨膜趋化因子(Bazan等人，1997；Panet et 等人，1997年)，并被ADAM10切割(Hurst等人，2012；Hundhausen等人，2003)以释放其N-末端 包含C-XXX-C基序的片段，该基序介导与G蛋白偶联的CX3CR1受体(IMAI)的结合 等人，1997年)。自从CX3CL1被发现以来，其生物学功能已被独家证明存在 通过CX3CL1/CX3CR1相互作用，激活信号转导调节炎症反应， 白细胞的捕获和渗透以及其他免疫功能。然而，我们发现，C- 末端结构域具有反向信号功能，它调节对细胞生长重要的基因的表达 或差异化。我们的目标是验证CX3CL1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，从而补充神经元的丢失并促进神经功能的恢复 阿尔茨海默病小鼠模型的突触功能。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)在神经发生控制中的作用；目标2：增强 神经发生逆转AD小鼠模型中受损的突触功能；和目标3：探索潜在的 CX3CL1-ct在AD治疗中年龄依赖性神经发生中的治疗应用。完成实验 这将为CX3CL1在AD治疗中的翻译潜力提供新的答案。知识 这项研究将指导作为AD联合疗法靶向的分子的未来发展 不仅会减少淀粉样蛋白的沉积或tau的聚集，而且还会补充神经元。