Aging microglia-neuronal communication

描述（由申请人提供）：该项目的总体目标是定义促进神经退行性疾病状态建立的胶质细胞表型。提出的实验将详细了解与年龄相关的神经胶质激活状态的变化以及它们如何受到神经炎症刺激的影响。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理解神经退行性疾病发病机制中涉及的炎症机制的关键。微小的微环境改变可以诱导小胶质细胞迅速反应，改变形态并获得一系列功能，包括吞噬和炎症分子的分泌。这种激活的后果必须严格调节，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作，被精心安排和调节，直到，由于正常的衰老，有一个逐渐转变到一个非平衡状态，允许神经退行性过程。目的1将使用一系列区分促炎性或抗炎性小胶质细胞状态的标记物，确定与正常衰老或脑室内LPS输注相关的小胶质细胞激活的时间过程和表型谱的区域变化。目的2将研究神经元调节小胶质细胞因子谱的三种特定机制，这些机制对LPS挑战的反应以及它们如何随着正常衰老而改变。目的3将研究咖啡因在年轻和老年雄性大鼠中恢复细胞因子平衡和促进抗炎细胞因子分布以及改善空间记忆的能力。目的4将研究炎症诱导的nmda型谷氨酸受体依赖性钙离子信号改变的后果。我们假设这些变化的模式，以及随后发展的退行性变化，可能是由于微环境的区域变化，这是激活的小胶质细胞或受伤的神经元释放促炎和抗炎分子的能力的直接后果，以响应它们的年龄和与神经元沟通的能力。如果一个八岁的孩子摔倒并遭受头部创伤，一种短暂的、可控的炎症反应就会产生，以对抗任何神经元损伤。如果一个80岁的成年人跌倒并遭受头部创伤，炎症反应既不短暂也不受控制，非特异性的旁观者损伤是常见的。我们提出两个关键因素区分这些条件：衰老和神经元和胶质细胞沟通能力的丧失，以协调其反应的减少。在年轻的、未受伤的大脑中，神经元可以维持神经胶质处于静止状态。我们推测，这种对炎症信号的相互交流的失败导致小胶质细胞的不适当激活和细胞因子和自由基水平的增加，从而驱动自我传播的毒性循环，其中蛋白质聚集和异常细胞成分促进炎症介质的释放，从而加剧局部神经元损伤。该项目的总体目标是确定促进神经退行性疾病状态建立的胶质细胞表型。提出的实验将详细了解与年龄相关的神经胶质激活状态的变化以及它们如何受到神经炎症刺激的影响。总的来说，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理解神经退行性疾病发病机制中涉及的炎症机制的关键。

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.