Early Events in Alzheimer Pathogenesis

描述(申请人提供)：该计划提供了令人信服的证据，证明神经元和神经胶质细胞之间的相互作用是一个自我放大的循环，主要是由神经炎性细胞因子作为阿尔茨海默病(AD)发病的驱动因素；其中最主要的是白细胞介素1(IL-1)。我们把重点放在这个循环的入口点上，也就是说，给定神经元与其局部环境相互作用的电路中的早期事件。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，阿尔茨海默病的病理最初与神经元载脂蛋白E(ApoE)和淀粉样前体蛋白(APP)的升高有关。细胞培养中的实验研究表明，组织中的APP/ApoE反应是由于一种因果关系，其中APP的表达依赖于ApoE的共同表达，ApoE e3比ApoE e4更有效，并受IL-1的调节。神经元APP的升高伴随着APP碎片的分泌，APP碎片激活小胶质细胞并导致谷氨酸释放。综上所述，这表明谷氨酸-载脂蛋白E-APP轴在对不利刺激和神经炎症的早期神经元反应中被初始化。根据这些结果，我们惊讶地发现：i)当一个人在时间或空间上接近成熟的A？斑块时，神经元体中APP的表达下降；以及ii)在存在或清除A？斑块后，阿尔茨海默病脑中胶质细胞的激活持续存在。综上所述，这些数据启发了一个假设，该假说统一了当前该计划的更新：神经元对不利刺激的典型急性时相反应是通过ApoE和？app表达之间的协调、因果关系提高ApoE和？app的表达，这种关系在AD发病机制中变得不耦合，导致神经元？app不足，并倾向于做出不适当的细胞反应，并屈服于由小胶质细胞“经典”激活所造成的兴奋毒性应激。在项目1中，将使用人体组织和模型系统来识别和阐明谷氨酸-载脂蛋白E-APP轴的基本元素，以及IL-1在AD失败中的作用。项目2将在两个独特的群体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和蛋白质表达谱中的反映程度。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基因多态对这种激活的不同调节。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)和分子/生化样本分析(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，以开发合理的AD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.