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， 这在很大程度上是通过淀粉样斑块、神经纤维缠结和 进行性发展的神经元丢失。神经元丢失是一种与年龄相关的事件， 加剧突触丢失并导致严重的认知功能障碍。治疗性的 对阿尔茨海默病治疗的干预不仅应该减少淀粉样蛋白等阿尔茨海默病的病理特征 沉积和tau聚集，但也减轻突触损伤和神经变性。 本方案侧重于CX3CL1 C-末端结构域的临床前治疗探索 (CX3CL1-ICD)，具有诱导神经发生和神经保护的活性。我们有 最近发现一种CX3CL1-ICD衍生肽(Tet34)可诱导胰岛素激活 受体底物-1(IRS-1)和IRS-2，及其下游分子Akt和Foxos。 令人惊讶的是，用这种多肽处理的神经细胞显示出显著的减轻细胞压力， 寡聚Aβ诱导的细胞色素C释放和caspase3的裂解。 因此，Tet34可减轻细胞凋亡和A-β诱导的细胞毒性。在这份续期建议中，我们 将检验一种假设，即源自CX3CL1的多肽具有翻译能力 通过减少细胞压力，增强神经功能来改善认知功能的潜力 分化和减少tau介导的神经变性。具体地说，我们将回答 关于CX3CL1的N端和C端片段是否具有不同的细胞功能的问题， 这可能会拮抗CX3CL1在神经元中的有益作用。我们还将探索 CX3CL1依赖ICD的成人和大鼠神经发生的生化机制 突触调节。从这项研究中获得的知识将使我们能够探索我们的长期 最终目标是发现更多可用于治疗AD的特定分子 病人。为了检验我们的假设，我们将使用多种方法来解决 以下三个具体目标：目标1：鉴定CX3CL1C- 用于减少AD病理的终端域(CX3CL1-ICD)；目的2：确定N- CX3CL1末端和C末端对阿尔茨海默病模型小鼠tau病理的影响不同； 目的3：探讨CX3CL1-ICD基因调控的分子机制 表情。通过完成建议的实验，我们将获得将揭示 CX3CL1-ICD在AD发病机制中的作用

Abstract Alzheimer’s disease (AD) is the most common age-dependent neurodegenerative disease, which is largely recognized by the presence of amyloid plaques, neurofibrillary tangles, and progressive development of neuronal loss. Neuronal loss is an age-associated event, which exacerbates the loss of synapses and causes severe cognitive dysfunction. Therapeutic intervention for AD treatment should not only reduce AD pathological hallmarks such as amyloid deposition and tau aggregation, but also mitigate synaptic impairment and neurodegeneration. This proposal focuses on pre-clinical therapeutic exploration of C-terminal domain of CX3CL1 (CX3CL1-ICD), which has an activity for inducing neurogenesis and neuroprotection. We have recently discovered that a CX3CL1-ICD-derived peptide (Tet34) induces activation of insulin receptor substrate-1 (IRS-1) and IRS-2, and its downstream molecules, Akt and Foxos. Strikingly, neuronal cells treated with this peptide exhibited significantly reduced cell stress, cytochrome C release and cleavage of caspase 3, induced by the oligomeric Aβ treatment. Hence, Tet34 attenuates apoptosis and Aβ-induced cellular toxicity. In this renewal proposal, we will test the hypothesis that peptides derived from C-terminal CX3CL1 have the translational potential for improving cognitive functions by decreasing cellular stress, enhancing neural differentiation and reducing tau-mediated neurodegeneration. Specifically, we will answer the question of whether N- and C-terminal fragments of CX3CL1 have differential cellular functions, which potentially antagonize the beneficial effect of CX3CL1 in neurons. We will also explore the biochemical mechanisms underlying CX3CL1-ICD-dependent neurogenesis in adult and synaptic regulation. The knowledge gained from this study will allow us to explore our long-term and ultimate goal, which is to discover more specific molecules that can be used to treat AD patients. To test our hypothesis, we will employ multiple approaches to address questions in the following three specific aims: Aim 1: To identify potent short peptides derived from CX3CL1 C- terminal domain (CX3CL1-ICD) for reducing AD pathology; Aim 2: To determine whether N- terminal and C-terminal CX3CL1 have differential effects on tau pathology in AD mouse models; Aim 3: To determine the molecular mechanism underlying CX3CL1-ICD in the control of gene expression. By accomplishing experiments as proposed, we will gain knowledge that will reveal the role of CX3CL1-ICD in the control of AD pathogenesis.