Aging microglia-neuronal communication

描述(由申请人提供)：这个项目的总体目标是定义促进神经退行性疾病状态建立的神经胶质表型。拟议中的实验将建立一个详细的了解与年龄相关的胶质细胞激活状态的变化，以及它们如何受到神经炎性刺激的影响。这些研究的主要焦点是小胶质细胞与神经元的相互作用。脑细胞间的串扰可能是了解神经退行性疾病发病机制的关键。微妙的微环境变化可以诱导小胶质细胞快速反应，改变形态，获得一系列功能，包括吞噬和分泌炎症分子。这种激活的后果必须受到严格控制，因为反应不足和过度都可能导致病理后果。这些过程的平衡在几十年的时间尺度上运行，经过精心编排和调节，直到由于正常衰老，逐渐转变为允许神经退化过程的非平衡状态。目的1将使用一系列区分促炎或抗炎小胶质细胞状态的标记物，确定与正常衰老或内毒素脑室注射相关的小胶质细胞激活的时间进程和局部表型变化。目的2将研究神经元调节小胶质细胞因子谱的三种具体机制，这些机制对内毒素攻击的反应，以及它们是如何被正常衰老改变的。目的3研究咖啡因对年轻和老年雄性大鼠恢复细胞因子平衡、促进抗炎细胞因子谱和改善空间记忆的能力。目的4将研究炎症诱导的NMDA型谷氨酸受体依赖的钙离子信号的改变的后果。我们假设，这些变化的模式，以及随后发展的退行性变化，可能是由于微环境中的区域性变化，这是激活的小胶质细胞或受损神经元释放促炎和抗炎分子的能力的直接结果，以响应他们的年龄和与神经元沟通的能力。如果一个8岁的孩子摔倒并遭受头部创伤，就会产生一种短暂的、可控的炎症反应来对抗任何神经元损伤。如果一个80岁的成年人摔倒并遭受头部创伤，炎症反应既不短暂也不受控制，旁观者对神经纤维束的非特异性损伤是常见的。我们提出了两个关键因素来区分这些情况：衰老和神经元和神经胶质细胞为协调其反应的减少而进行适当沟通的能力的丧失。在年轻的、未受损伤的大脑中，神经元可能会保持胶质细胞的静止状态。我们推测，对炎症信号做出反应的这种相互联系的失败会导致小胶质细胞的不适当激活，以及细胞因子和自由基水平的增加，从而驱动一个自我传播的毒性循环，在这个循环中，蛋白质聚集和异常的细胞成分释放炎症介质，进而加剧局部神经元损伤。这个项目的总体目标是定义促进神经退行性疾病状态建立的神经胶质表型。拟议的实验将建立一个详细的了解与年龄相关的胶质细胞激活状态的变化，以及它们是如何受到神经炎性刺激的影响的。总体而言，这些研究的主要焦点是小胶质细胞与神经元的相互作用。脑细胞间的串扰可能是了解神经退行性疾病发病机制的关键。

DESCRIPTION (provided by applicant): The overall goal of this project is to define the glia phenotype that promotes the establishment of neurodegenerative disease states. The proposed experiments will establish a detailed understanding of age-related changes in glial activation states and how they are influenced by a neuroinflammatory stimulus. The primary focus of these studies is the interaction of microglia with neurons. Cross-talk among brain cells may be key for the understanding of inflammatory mechanisms involved in pathogenesis of neurodegenerative diseases. Subtle micro-environmental alterations can induce microglia to react rapidly, change morphology and acquire an array of functions, including phagocytosis and the secretion of inflammatory molecules. The consequences of this activation must be tightly regulated because both inadequate and excessive responses can result in pathological consequences. The balance of these processes, operating across a time scale of decades, are carefully orchestrated and regulated until, due to normal aging, there is a gradual shift to a non-equilibrium state that is permissive for neurodegenerative processes. Aim 1 will determine the time course and regional changes in phenotype profile of the microglial activation associated with normal aging or the intraventricular infusion of LPS using a series of markers that discriminate pro- or anti-inflammatory microglia states. Aim 2 will investigate three specific mechanisms by which neurons regulate the microglial cytokine profile, the response of these mechanisms to challenge by LPS and how they are altered by normal aging. Aim 3 will examine the ability of caffeine to restore cytokine balance and promote an anti-inflammatory cytokine profile in young and aged male rats and improve spatial memory. Aim 4 will investigate the consequences of inflammation-induced alterations in NMDA-type glutamate receptor- dependent calcium ion signaling. We hypothesize that the pattern of these changes, and the degenerative changes that subsequently develop, may be due to regional variations in the micro-environment that are a direct consequence of the ability of activated microglia or injured neurons to release pro- and anti-inflammatory molecules in response to their age and ability to communicate with neurons. If an eight years old child falls and sustains head trauma, a brief, controlled inflammatory response develops to combat any neuronal injury. If an eighty year old adult falls and sustains head trauma, the inflammatory response is neither brief nor controlled and nonspecific bystander injury to the neuropil is common. We propose that two critical factors distinguish these conditions: aging and the loss of the ability of neurons and glia to communicate appropriately in order to coordinate a decrease in their response. Neurons may maintain glia in a quiescent state in the young, uninjured brain. We speculate that a failure in this intercommunication in response to an inflammatory signal results in the inappropriate activation of microglia and increased levels of cytokines and free radicals that drive a self propagating toxic cycle in which protein aggregates and abnormal cellular components promulgate the release of inflammatory mediators which in turn exacerbate local neuronal injury. The overall goal of this project is to define the glia phenotype that promotes the establishment of neurodegenerative disease states. The proposed experiments will establish a detailed understanding of age related changes in glial activation states and how they are influenced by a neuroinflammatory stimulus. Overall, the primary focus of these studies is the interaction of microglia with neurons. Cross talk among brain cells may be key for the understanding of inflammatory mechanisms involved in pathogenesis of neurodegenerative diseases.