GLIAL NEURONAL INTERACTION IN ALZHEIMERS DISEASE

阿尔茨海默病中的胶质神经元相互作用

基本信息

批准号：
6098591
负责人：
Sue Tilton Griffin
金额：
$ 15.3万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-06-01 至 2000-05-31
项目状态：
已结题

项目摘要

The objective of Project 1 is to address the idea that glial inflammatory changes with over-expression of glia-derived cytokines, in particular interleukin-1 (IL-1) and S100beta, are primer movers in a cascade of events that lead to neuronal cell injury and death in the early pathogenesis of Alzheimer's disease (AD). These cytokine-driven cascades of neuronal dysfunctions include early over-expression of betaAPP, accumulation of neurofibrillary tangles, overgrowth of betaAPP- over-expressing neurites, appearance of neuropil threads, and eventually cell death. Chronic activation of these cytokine-drive neurodegenerative cascades can in turn promote further over-expression of IL-1. In this way these cytokine-driven cascades may become self-propagating as illustrated in the "cytokine cycle". To elucidate aspects of this cycle, we will use molecular techniques to: 1) Define the relationship of glial inflammation to neuronal cell injury (as evidenced by betaAPP over- expression and neurofibrillary tangle formation in neurons, neurites and in neuropil threads, as well as by synaptic changes) and neuronal cell death (as evidenced by TUNEL positivity) in Alzheimer's disease. These will be correlated with the incidence of: i) associated activated microglial over-expression IL-i); ii) associated activated microglia over-expressing IL-1; ii) associated activated astrocytes over- expressing S100beta; iii) associated beta-amyloid plaques of different types; and iv) stages of neurofibrillary tangle formation. 2) Define the temporal and spatial relationships of glial inflammation to neuronal cell injury and death in conditions predisposing to Alzheimer's disease or to accelerated Alzheimer-type senile changes. For this we will use material from patients with Braak and Braak stages of I-IV of Alzheimer- related changes, with Down's syndrome, with head injury, and with epilepsy. 3) Examine the extent and nature of altered glial cytokine expression and of neuronal cell injury and death in genetic animal models with altered expression of cytokine cycle elements. These include betaAPP transgenic mice and S100beta transgenic mice. 4) Assess the local and remote effects of exogenous glial cytokines in vivo, using intracerebral implants of timed-release pellets containing specific glial cytokines and other cytokine cycle molecules. Successful completion of these specific aims will provide information regarding the progression of neuropathological changes and highlight targets for therapeutic strategies to slow the clinical progression of Alzheimer's disease.

项目 1 的目标是解决以下观点：神经胶质细胞衍生的细胞因子（特别是白细胞介素 1 (IL-1) 和 S100β）的过度表达导致神经胶质炎症变化，是导致神经元细胞发生一系列事件的引物。阿尔茨海默病 (AD) 早期发病机制中的损伤和死亡。这些细胞因子驱动的神经元功能障碍级联包括βAPP的早期过度表达、神经原纤维缠结的积累、βAPP过度表达的神经突的过度生长、神经纤维丝的出现以及最终的细胞死亡。这些细胞因子驱动的神经退行性级联反应的慢性激活反过来又会促进 IL-1 的进一步过度表达。通过这种方式，这些细胞因子驱动的级联可能会自我繁殖，如“细胞因子循环”所示。为了阐明这个循环的各个方面，我们将使用分子技术来：1）定义神经胶质炎症与神经元细胞损伤的关系（如神经元、神经突和神经毡线中的 betaAPP 过度表达和神经原纤维缠结形成所证明的）阿尔茨海默病中的突触变化）和神经元细胞死亡（TUNEL 阳性证明）。这些将与以下的发生率相关：i)相关的激活的小胶质细胞过度表达IL-i)； ii) 相关的活化小胶质细胞过表达 IL-1； ii)相关的活化星形胶质细胞过度表达S100beta； iii) 不同类型的相关β-淀粉样斑块； iv) 神经原纤维缠结形成的阶段。 2) 定义在易患阿尔茨海默病或加速阿尔茨海默型老年变化的情况下，神经胶质炎症与神经元细胞损伤和死亡的时间和空间关系。为此，我们将使用患有阿尔茨海默病相关变化 I-IV 期 Braak 和 Braak 阶段、唐氏综合症、头部损伤和癫痫患者的材料。 3) 检查细胞因子周期元件表达改变的遗传动物模型中神经胶质细胞因子表达改变以及神经元细胞损伤和死亡的程度和性质。这些包括 betaAPP 转基因小鼠和 S100beta 转基因小鼠。 4) 使用含有特定神经胶质细胞因子和其他细胞因子周期分子的定时释放颗粒的脑内植入物，评估外源性神经胶质细胞因子在体内的局部和远程影响。成功完成这些具体目标将提供有关神经病理学变化进展的信息，并突出减缓阿尔茨海默病临床进展的治疗策略的目标。