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：
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
项目类别：
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&apos s Disease Alzheimer&apos 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

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.

抽象的阿尔茨海默氏病（AD）是最常见的年龄依赖性神经退行性疾病在广告大脑中丢失仍然有争议，Althooth许多研究假设有毒β-淀粉样蛋白肽（Aβ）以各种形式（例如可溶性多聚体或低聚物）以及tau syergate有助于神经元衰老的大脑损失和AD AD鼠标模型中的突触功能障碍。一定会发展依赖年龄的神经发电，支持上述攻击。为了阻止或去除淀粉样蛋白沉积或TAU聚集的药物。调查如何通过逆转作为替代策略来恢复神经元损失退化过程。（TG-CX3CL1）或CX3CL1（TG-CX3CL1-CT）的C末端结构域显示出增强的神经发生。 CX3CL1，也称为Fractalkine，是I型跨膜趋化因子（Bazan等，1997; Pan Ett Al。，1997），并由ADAM10裂解（Hurst等，2012； Hundhausen等。片段含有C-XXX-C基序，该基序介导了与G蛋白组合的CX3CR1受体（IMAI）结合的片段等，1997）。通过CX3CL1/CX3CR1相互作用，激活信号转导向调节炎症反应，白细胞船长和浸润以及其他免疫功能。末端结构域具有后信号函数，调节基因的表达对细胞生长很重要或区分。我们旨在测试CX3CL1的神经元表达的假设神经发生通过其C末端结构域，该结构域补充了神经元丧失并促进了恢复 AD鼠标模型中的突触功能。确定CX3CL1 C末端结构域（CX3CL1-CT）在神经发生中的作用；在AD小鼠模型中，神经发生以反向逆转突触功能； CX3CL1-CT在年龄依赖性神经发生中的治疗用途作为支撑物将主要针对CX3CL1在AD治疗中的翻译潜力从研究中获得的将指导Fuide Fuide Fuide Fuide Fuide Fuide Fuide Fuide Fuide Fuide Fuide Talecules作为AD组合的目标不仅会沉积或tau聚集，而且还将补充神经元。