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：
6324545
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：
2000
资助国家：
美国
起止时间：
2000-07-01 至 2001-05-31
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的目的是解决以下观点：胶质炎性变化随着神经胶质衍生的细胞因子的过表达，尤其是白介素-1（IL-1）和S100BETA，是一系列级联事件中的底漆转推，这些事件导致神经元细胞损伤和死亡，导致Alzheimer病早期病原体（AD）的早期病原（AD）。这些神经元功能障碍的细胞因子驱动的级联反应包括βApp的早期表达，神经原纤维缠结的积累，βApp过度表达神经突的过度生长，神经皮质线的外观以及最终的细胞死亡。这些细胞因子驱动神经退行性级联反过来又可以促进IL-1的过度表达。通过这种方式，这些细胞因子驱动的级联反应可能会自我传播，如“细胞因子循环”中所示。 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.这些将与：i）相关的活化的小胶质过表达IL-i）的发生率相关； ii）相关的活化的小胶质细胞过表达IL-1； ii）相关的激活的星形胶质细胞过度表达s100beta； iii）不同类型的相关β-淀粉样木斑块；和iv）神经纤维缠结形成的阶段。 2）在易感阿尔茨海默氏病或加速阿尔茨海默氏症型老年变化的情况下，定义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，我们将使用与阿尔茨海默氏症相关变化的I-IV的Braak和Braak阶段的材料，以及唐氏综合症，头部受伤和癫痫病。 3）检查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，其遗传动物模型的表达改变了细胞因子循环元素。其中包括βApp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体内外源性神经胶质细胞因子的局部和远程作用。这些特定目标的成功完成将提供有关神经病理学变化进展的信息，并突出了治疗策略的目标，以减缓阿尔茨海默氏病的临床进展。