Neuronal-Glial Dialogue and Cognition

神经元-胶质细胞对话和认知

基本信息

批准号：
8318595
负责人：
CARMELINA GEMMA
金额：
$ 15.84万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8318595
关键词：
Address Adult Age Aging Animals Anti-Inflammatory Agents Anti-inflammatory Attenuated Binding Biological Blood - brain barrier anatomy Brain CX3C Chemokines CX3CL1 gene Cell Proliferation Cells Cognition Cognitive Cognitive aging Communication Data Defect Early treatment Encephalitis Evaluation Event Feedback Fractalkine Functional disorder Gene Expression Genes Goals Hippocampus (Brain)Immune system Impaired cognition Impairment Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-6 Lead Learning Leukocytes Ligands MAPK14 gene Memory Memory Loss Memory impairment Microglia Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurons Pathologic Processes Pathway interactions Patients Peripheral Phenotype Physiological Plasma Play Process Production Proteins Publishing Rattus Recombinant Delta Chemokine Recombinant adeno-associated virus (rAAV)Research Rest Role Signal Transduction Synaptic plasticity System TNF gene Testing Time Toxic effect Wild Type Mouse Work age related aged aging brain base chemokine cognitive change cognitive function cytokine dentate gyrus design functional disability genetic regulatory protein improved inflammatory marker insight nerve stem cell nervous system disorder neurogenesis neuroinflammation neuroprotection neurotoxic normal aging novel novel strategies receptor

项目摘要

DESCRIPTION (provided by applicant): Fractalkine, is a chemokine expressed constitutively by healthy neurons and it has been identified as a novel neuroimmune regulatory protein, whose function is to send alert signals to microglia, and inhibit microglia activity under inflammatory conditions. Disruption of this dialogue could trigger more drastic changes in the functional phenotype of microglia. In contrast to many other chemokines, fractalkine binds to only one receptor (CX3CR1). Evaluation of several pathological processes that did not involve blood brain barrier compromise (and therefore did not entail large scale entry of peripheral leukocytes) showed that signaling through the CX3CR1 receptor reduced neuronal damage. It has also been shown that fractalkine controls the degree of microglia toxicity by attenuating the production of IL-1¿?and TNFa. The specific hypothesis addressed in this application is that a disruption in the crosstalk between neuronally-derived fractalkine and microglial cell expressed CX3CR1 leads to microglia overactivation by pushing the cytokine profile away from a M2/alternative state towards the M1/classical state, and that IL-1¿??is one of the key molecules responsible for the deleterious effect of disruption of CX3CR1/fractalkine signaling on cognitive function. Our working hypothesis is supported by our published data in which we show for the first time that there is a decrease in soluble fractalkine protein levels in the aged brain and this may be one of the key players that is disrupted with age, thereby leading to overactivation of the innate immune system. We have further demonstrated that administering fractalkine to aged rats increases proliferation of endogenous neuronal progenitors in the subgranular zone of the dentate gyrus, while blocking the function of CX3CR1 in young rats decreases neuronal progenitor cell proliferation in the subgranular zone. In addition we have new preliminary data showing that CX3CR1-/- mice in non-pathological conditions have reduced synaptic plasticity in the form of decreased neurogenesis and most recently that these mice show reduced LTP and deficits in cognitive function. To the best of our knowledge, there are no data from studies other than ours directly investigating the role of FKN on learning and memory in aged rats. We hypothesize that aging leads to a disruption in CX3CR1/fractalkine signaling, which triggers an increase in IL-1¿ levels. This positive feedback loop leads to neuroinflammation and contributes to impaired cognition. Here, we will test this hypothesis by pursuing the following two specific aims: 1) Microglial dysfunction in CX3CR1-deficient (CX3CR1-/-) mice and increased levels of IL-1¿ lead to functional impairment in cognitive function; 2) Impairment in Fractalkine/CX3CR1 signaling modulates hippocampal-dependent age-related memory deficits. Our contribution here is expected to be a detailed understanding of how FKN/CX3CR1 signaling defect in the aged brain leads to a decline in cognitive function.

描述（申请人提供）：Fractalkine是一种由健康神经元组成型表达的趋化因子，已被鉴定为一种新型神经免疫调节蛋白，其功能是向小胶质细胞发送警报信号，并在炎症条件下抑制小胶质细胞的活性。对话可能引发小胶质细胞功能表型的更剧烈变化与许多其他趋化因子相比，fractalkine 仅与一种受体（CX3CR1）结合。不涉及血脑屏障损害（因此不需要外周白细胞大规模进入）的病理过程表明，通过 CX3CR1 受体的信号传导减少了神经元损伤，还表明 fractalkine 通过减弱神经元损伤来控制小胶质细胞的毒性程度。 IL-1的生产¿本申请提出的具体假设是，神经元衍生的 fractalkine 和小胶质细胞表达的 CX3CR1 之间的串扰通过将细胞因子谱从 M2/替代状态推向 M1/经典状态而导致小胶质细胞过度激活。，以及 IL-1¿是导致 CX3CR1/fractalkine 信号破坏对认知功能产生有害影响的关键分子之一。我们的工作假设得到了我们发表的数据的支持，其中我们首次表明可溶性 fractalkine 蛋白减少。老年大脑中的水平，这可能是随着年龄的增长而受到干扰的关键因素之一，从而导致先天免疫系统过度激活，我们进一步证明，对老年大鼠施用弗莱托肯会增加内源性神经元的增殖。在年轻大鼠中，阻断 CX3CR1 的功能会减少齿状回颗粒下区的神经元祖细胞增殖，此外，我们有新的初步数据表明，非病理条件下的 CX3CR1-/- 小鼠的神经元祖细胞增殖有所减少。突触可塑性表现为神经发生减少，最近这些小鼠表现出 LTP 减少和认知功能缺陷，据我们所知，除此之外没有其他研究数据。我们直接研究了 FKN 对老年大鼠学习和记忆的作用，我们发现衰老会导致 CX3CR1/fractalkine 信号传导中断，从而引发 IL-1 的增加。这种正反馈循环会导致神经炎症并导致认知受损。在这里，我们将通过追求以下两个具体目标来检验这一假设：1) CX3CR1 缺陷 (CX3CR1-/-) 小鼠的小胶质细胞功能障碍和 IL 水平升高。 -1¿导致认知功能障碍；2）Fractalkine/CX3CR1 信号传导损伤调节海马依赖性年龄相关记忆缺陷，我们的贡献预计是详细了解老年大脑中的 FKN/CX3CR1 信号传导缺陷如何导致功能障碍。认知功能下降。