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：
10594845
负责人：
RIQIANG YAN
金额：
$ 213.27万
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：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594845
关键词：
Address Adult Age Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amino Acids Amyloid Amyloid beta-Protein Amyloid deposition Apoptosis Attenuated Back Binding Biochemical Biological Assay Brain Breeding C-terminal CASP3 gene CX3CL1 gene Cell Nucleus Cell physiology Cells Cellular Stress Cognitive Complementary DNA Complex Cultured Cells Development Elderly Elements Event Exhibits Fractalkine Gene Expression Genetic Transcription Genetic study Goals Human Impaired cognition Impairment In Vitro Insulin Receptor Knock-in Knock-in Mouse Knowledge Late Onset Alzheimer Disease Length Mediating Membrane Mitochondria Molecular Mus N-terminal Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Pathogenesis Pathologic Pathology Peptides Persons Pharmaceutical Preparations Phosphorylation Proteins Proteomics Receptor Signaling Regulation Research Role Senile Plaques Signal Transduction Synapses Tauopathies Testing Tetracycline Control Tetracyclines Therapeutic Therapeutic Intervention Toxic effect Transforming Growth Factor beta Transgenic Mice Validation abeta accumulation adult neurogenesis age related aging population beta-site APP cleaving enzyme 1 chemokine cofactor cognitive function crosslink cytochrome c experimental study gamma secretase improved in vivo insulin receptor substrate 1 protein mature animal mouse genetics mouse model neural neurogenesis neuroinflammation neuron apoptosis neuron development neuron loss neuroprotection overexpression pre-clinical promoter protein aggregation subventricular zone synaptic function synthetic peptide tau Proteins tau aggregation tau mutation tau-1 transcription factor transcriptome sequencing transcriptomics translational potential

项目摘要

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.

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，这在很大程度上通过淀粉样蛋白斑块，神经纤维缠结和神经元损失的逐步发展。神经元损失是与年龄相关的事件，该事件加剧突触的丧失，并导致严重的认知功能障碍。治疗性 AD治疗的干预措施不仅应降低AD病理标志，例如淀粉样蛋白沉积和tau聚集，但也减轻突触障碍和神经退行性。该建议重点介绍了CX3CL1 C末端结构域的临床前治疗探索（CX3CL1-ICD），它具有诱导神经发生和神经保护作用的活性。我们有最近发现，CX3CL1-ICD衍生的肽（TET34）会影响胰岛素的激活受体底物-1（IRS-1）和IRS-2及其下游分子AKT和FOXOS。令人惊讶的是，用这种肽暴露处理的神经元细胞显着降低了细胞应激，通过低聚Aβ诱导的caspase 3的细胞色素C释放和裂解。因此，TET34减弱了细胞凋亡和Aβ诱导的细胞毒性。在这个续签建议中，我们将检验以下假设，即从C末端CX3CL1衍生的肽具有翻译通过减少细胞应激来改善认知功能的潜力，增强神经元分化和减少tau介导的神经退行性。具体来说，我们将回答 CX3CL1的N-和C末端片段是否具有不同的细胞功能，这可能会拮抗CX3CL1在神经元中的有益作用。我们还将探索成人和突触调节。这项研究所获得的知识将使我们能够探索我们的长期和最终目标，即发现可用于治疗AD的更多特定分子患者。为了检验我们的假设，我们将采用多种方法来解决以下三个具体目的：目标1：确定从CX3CL1 C-衍生的潜在短肽用于减少AD病理学的末端结构域（CX3CL1-ICD）；目标2：确定n-是否在AD小鼠模型中，末端和C末端CX3CL1对TAU病理具有不同的影响；目标3：确定CX3CL1-ICD控制基因的分子机制表达。通过提出的实验，我们将获得知识，以揭示 CX3CL1-ICD在控制AD发病机理中的作用。