GLIAL NEURONAL INTERACTIONS IN CELL CULTURE MODELS

引发阿尔茨海默病的共同病理过程可能反映了细胞生物学基本方面的异常，因此可以通过细胞培养方法进行研究，这种方法提供了其他模型无法获得的操作程度（和速率）。在这个项目中，组织培养模型将用于测试在阿尔茨海默氏症中理论上可行的神经胶质和神经元相互作用的各个方面。初步星形胶质细胞和小胶质细胞培养、神经元培养和相关细胞系将用于分析细胞因子对其他项目中正在探索的参数的影响，因为它们在阿尔茨海默病和相关疾病的发生和/或进展中具有潜在的重要性。本项目的重点是假设s100 β和其他胶质细胞因子调节神经和突触的完整性，并且这种调节可能涉及致病性betaAPP的过表达。这些相互作用似乎是阿尔茨海默病病理和临床痴呆的根源；它们将通过三个具体目标进行探索。目的1：确定s100 β对betaAPP表达和加工的影响。初步研究表明，s100 β可以提高betaAPP，这对淀粉样蛋白沉积和异常神经细胞发生都有影响。拟议的研究将确定参与这种诱导的机制及其与神经突生长和淀粉样蛋白产生的相关性。目的2：确定细胞因子对钙稳态、神经鞘生长和突触之间相互作用的潜在影响。虽然s100 β提高了betaAPP，但它也可能通过影响钙水平对神经元过程和连接产生不相关的影响。其他细胞因子对这些参数也有更普遍的影响。确定抗炎细胞因子和药物对神经胶质和神经元激活的有效性。aim 3的主要终点将是小胶质细胞的激活，目的是减少对神经元健康和功能产生负面影响的细胞因子和神经毒素的产生。然而，也有可能促炎细胞因子对神经元的直接作用可能容易受到靶向基本细胞因子信号事件的药物的操纵。这些目标的实现将直接有利于确定阿尔茨海默病病理的基本要素和治疗干预的潜在位点。

The shared pathological processes that initiate Alzheimer's disease likely reflect aberrancies in basic aspects of cell biology and thus are amenable to study through cell culture approaches, which offer a degree (and rate) of manipulation unavailable in other models. In this project, tissue culture models will be used to test various aspects of glial and neuronal interactions theoretically operative in Alzheimer's. Preliminary astroglial and microglial culture, neuronal cultures, and relevant cell lines will be utilized to assay the effects of cytokines on parameters being explored in other projects because of their potential importance in the initiation and/or progression of Alzheimer's and related conditions. This project is focused on the hypothesis that S100beta and other glial cytokines modulate neuritic and synaptic integrity, and that this modulation can involve pathogenic over- expression of betaAPP. These interactions appear to be at the root of Alzheimer pathology and clinical dementia; they will be explored through three specific aims. Aim 1: Determine the effects of S100beta on expression and processing of betaAPP. Initial studies have shown that S100beta can elevate betaAPP, which has implications for both amyloid deposition and aberrant neuritogenesis. Proposed studies will determine mechanisms involved in this induction and its relevance to neurite growth and amyloid production. Aim 2: Determine the potential influence of cytokines on the interaction between calcium homeostasis, neuritic outgrowth, and synapses. While S100beta elevates betaAPP, it also could have unrelated effects on neuronal processes and connections through its impact on calcium levels. A more general influence on these parameters is indicated for other cytokines, as well. Determine the effectiveness of anti-inflammatory cytokines and rugs against glial and neuronal activation. The primary endpoint in aim 3 will be microglial activation, with the goal of reducing production of cytokines and neurotoxins which negatively impact neuronal health and function. However, it is also plausible that direct effects of pro-inflammatory cytokines on neurons may be susceptible to manipulation by drugs that target basic cytokine signaling events. Accomplishment of these goals will be of direct benefit to the identification of basic elements of Alzheimer's pathology and potential sites for therapeutic intervention.