Early Events in Alzheimer Pathogenesis

描述（由申请人提供）：该项目提供了令人信服的证据，证明神经元和神经胶质之间相互作用的自我放大周期，主要由神经炎症细胞因子介导，作为阿尔茨海默病（AD）发病机制的驱动因素；其中主要是白细胞介素-1 （IL-1）。我们关注的是这个循环的入口点，也就是说，在给定神经元与局部环境相互作用的回路中，早期发生的事件。最近对人体组织和新获得的转基因阿尔茨海默病模型的检查表明，阿尔茨海默病型的病理最初与载脂蛋白E （ApoE）和淀粉样蛋白前体蛋白（APP）的神经元升高有关。细胞培养的经验研究表明，组织中的¿APP/ApoE反应是由于¿APP表达依赖于ApoE共表达的因果关系，ApoE e3比ApoE e4更有效，并受IL-1调节。神经元¿APP升高伴随着¿APP片段的分泌，其激活小胶质细胞并引起谷氨酸释放。总之，这表明谷氨酸- apoe - APP轴在对不良刺激和神经炎症的早期神经元反应中被初始化。通过这些结果，我们惊讶地发现，i)当一个人接近成熟的A¿斑块时，神经元体中的APP表达会下降，无论是在时间上还是在空间上；ii)在A¿斑块存在或“清除”之后，阿尔茨海默病大脑中的神经胶质激活持续存在。总之，这些数据激发了一个统一当前该计划更新的假设：神经元对不良刺激的典型急性期反应是通过ApoE和APP表达之间的协调因果关系来提高ApoE和¿APP表达，而ApoE和¿APP表达在AD发病机制中变得不耦合，使神经元缺乏¿APP并倾向于做出不适当的细胞反应，并屈服于小胶质细胞“经典”激活所造成的兴奋毒性应激。项目1将使用人体组织和模型系统来识别和阐明谷氨酸- apoe -¿APP轴的基本元素，以及IL-1在AD中的作用。项目2将在两个独特的种群中确定小胶质细胞激活和细胞因子释放的共同途径，以及这种激活在mRNA和蛋白质表达谱中反映的程度。项目3将研究与谷氨酸氧化产生相关的小胶质细胞激活的关键方面，以及IL-1a基因多态性对这种激活的差异调节。三个核心为这些研究提供行政协调（核心A），组织银行和处理（核心B）以及分子/生化样品分析（核心C）。我们的目标，方法和措施之间的协同作用将使我们能够实现我们的目标，即定义早期细胞相互作用，以开发AD的合理干预措施。

DESCRIPTION (provided by applicant): This Program has provided compelling evidence for a self amplifying cycle of interactions between neurons and glia, mediated largely by neuroinflammatory cytokines acting as drivers of Alzheimer's disease (AD) pathogenesis; chief among these is interleukin-1 (IL-1). We have focused on the entry points into this cycle, which is to say the early events in a given neuron's circuit of interactions with its local environs. Recent examinations of human tissue and of a newly acquired transgenic Alzheimer model indicate that pathology of the Alzheimer type is initially associated with neuronal elevation of apolipoprotein E (ApoE) and ¿-amyloid precursor protein (¿APP). Empirical studies in cell culture suggest that the ¿APP/ApoE response in tissue is due to a causal relationship in which ¿APP expression is dependent on co-expression of ApoE, with ApoE e3 more efficacious than ApoE e4, and is modulated by IL-1. Neuronal ¿APP elevation is accompanied by secretion of ¿APP fragments, which activate microglia and cause glutamate release. Together, this suggests that a glutamate-ApoE-¿APP axis is initialized in the early neuronal responses to adverse stimuli and neuroinflammation. With these results, we were surprised to find that i) ¿APP expression declines in neuronal somata as one approaches mature A¿ plaques, either temporally or spatially; and ii) glial activation persists in Alzheimer brain in the presence or following "clearance" of A¿ plaques. Together, these data inspire a hypothesis that unifies the current renewal of this Program: The typical acute-phase response of neurons to adverse stimuli is to elevate ApoE and ¿APP expression via a coordinated, causal relationship between ApoE and ¿APP expression that becomes uncoupled in AD pathogenesis, leaving neurons with insufficient ¿APP and a propensity to make inappropriate cellular responses and to succumb to the excitotoxic stress perpetrated by "classical" activation of microglia. Human tissue and model systems will be used in Project 1 to identify and elucidate the basic elements of the glutamate-ApoE-¿APP axis, and the role of IL-1 in its failure in AD. Project 2 will identify, in two unique populations, common pathways for microglial activation and cytokine release and the degree to which this activation is reflected in mRNA and protein expression profiles. Project 3 will investigate key aspects of microglial activation related to oxidative production of glutamate and the differential modulation of this activation by IL-1a gene polymorphisms. Three cores provide administrative coordination (Core A), tissue banking and processing (Core B), and molecular/biochemical sample analyses (Core C) for these studies. The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD.