Neuronal-Glial Dialogue and Cognition

描述(申请人提供)：Fractalkine是一种由健康神经元结构性表达的趋化因子，已被鉴定为一种新的神经免疫调节蛋白，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动。这种对话的中断可能会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不同，Fractalkine只与一个受体(CX3CR1)结合。对几个不涉及血脑屏障损害(因此不需要外周血白细胞大规模进入)的病理过程的评估表明，通过CX3CR1受体发出的信号减少了神经元损伤。研究还表明，Fractalkine通过减少IL-1和TNFa的产生来控制小胶质细胞的毒性程度。这一应用中涉及的特定假设是，神经元来源的Fractalkine与小胶质细胞表达的CX3CR1之间的串扰中断导致小胶质细胞过度激活，将细胞因子谱从M2/替代状态推向M1/经典状态，IL-1β是CX3CR1/Fractalkine信号中断对认知功能产生有害影响的关键分子之一。我们的工作假说得到了我们公布的数据的支持，在这些数据中，我们首次表明，在衰老的大脑中，可溶性Fractalkine蛋白水平下降，这可能是随着年龄的增长而被破坏的关键因素之一，从而导致天然免疫系统的过度激活。我们进一步证明，给老年大鼠应用Fractalkine可增加齿状回颗粒下区内源性神经前体细胞的增殖，而阻断幼年大鼠CX3CR1的功能会降低颗粒下区神经前体细胞的增殖。此外，我们有新的初步数据显示，在非病理条件下，CX3CR1-/-小鼠的突触可塑性降低，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。就我们所知，除了我们的研究以外，没有其他研究直接调查FKN对老年大鼠学习和记忆的作用。我们假设衰老导致CX3CR1/Fractalkine信号的中断，从而触发IL-1水平的增加。这种正反馈环路会导致神经炎症，并导致认知受损。在这里，我们将通过追求以下两个特定目标来验证这一假说：1)CX3CR1缺陷(CX3CR1-/-)小鼠的小胶质细胞功能障碍和IL-1水平的增加导致认知功能的功能损害；2)Fractalkine/CX3CR1信号的损害调节海马区依赖的年龄相关的记忆缺陷。我们在这里的贡献有望详细理解FKN/CX3CR1信号缺陷是如何导致老年大脑认知功能下降的。

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.