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、神经原纤维缠结的存在来识别的神经元丧失的进行性发展是一种与年龄相关的事件。加剧突触损失并导致严重的认知功能障碍。对 AD 治疗的干预不应仅仅减少淀粉样蛋白等 AD 病理标志沉积和 tau 蛋白聚集，还可以减轻突触损伤和神经退行性变。该提案重点关注CX3CL1 C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。最近发现CX3CL1-ICD衍生肽（Tet34）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。引人注目的是，用这种肽处理的神经元细胞表现出显着降低的细胞应激，寡聚 Aβ 处理诱导细胞色素 C 释放和 caspase 3 裂解。因此，Tet34 可以减轻细胞凋亡和 Aβ 诱导的细胞毒性。将检验源自 C 端 CX3CL1 的肽具有翻译能力的假设通过减少细胞压力、增强神经功能来改善认知功能的潜力具体来说，我们将回答以下问题： CX3CL1 的 N 端和 C 端片段是否具有不同的细胞功能的问题，我们还将探讨这可能会拮抗 CX3CL1 对神经元的有益作用。成人CX3CL1-ICD依赖性神经发生的生化机制从这项研究中获得的知识将使我们能够探索我们的长期作用。最终目标是发现更多可用于治疗 AD 的特异性分子为了检验我们的假设，我们将采用多种方法来解决患者中的问题。以下三个具体目标：目标 1：鉴定源自 CX3CL1 C- 的有效短肽目的 2：确定是否 N- CX3CL1 末端和 C 末端对 AD 小鼠模型中 tau 病理学有不同的影响；目标3：确定CX3CL1-ICD控制基因的分子机制通过完成所提出的实验，我们将获得能够揭示的知识。 CX3CL1-ICD 在控制 AD 发病机制中的作用。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reticulons 1 and 3 are essential for axonal growth and synaptic maintenance associated with intellectual development.

网状细胞 1 和 3 对于与智力发育相关的轴突生长和突触维持至关重要。

DOI：
发表时间：
2023-08-07
期刊：
影响因子：
3.5
作者：
Zhou, John;Shi, Qi;Ge, Ying Y;He, Wanxia;Hu, Xiangyou;Xia, Weiming;Yan, Riqiang
通讯作者：
Yan, Riqiang

BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides.

BACE1 调节星形胶质细胞中 Clusterin 的表达，以增强 β-淀粉样肽的清除。

DOI：
发表时间：
2023-05-04
期刊：
影响因子：
15.1
作者：
Zhou, John;Singh, Neeraj;Galske, James;Hudobenko, Jacob;Hu, Xiangyou;Yan, Riqiang
通讯作者：
Yan, Riqiang

Postnatal neuronal Bace1 deletion impairs neuroblast and oligodendrocyte maturation.

出生后神经元 Bace1 缺失会损害神经母细胞和少突胶质细胞的成熟。

DOI：
发表时间：
2023-03-20
期刊：
影响因子：
3.5
作者：
Benoit, Marc R;Darboe, Mabintou;Das, Brati;Ge, Yingying;Zhou, John;Yao, Annie;He, Wanxia;Yan, Riqiang;Hu, Xiangyou
通讯作者：
Hu, Xiangyou

The CX3CL1 intracellular domain exhibits neuroprotection via insulin receptor/insulin-like growth factor receptor signaling.

CX3CL1 胞内结构域通过胰岛素受体/胰岛素样生长因子受体信号传导发挥神经保护作用。