GLIAL NEURONAL INTERACTION IN ALZHEIMERS DISEASE

阿尔茨海默病中的胶质神经元相互作用

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6324545
• 关键词: Alzheimer's disease; Downs syndrome; amyloid proteins; amyloidosis; astrocytes; cell cell interaction; cytokine; gene expression; genetic techniques; genetically modified animals; glia; head /neck injury; human tissue; inflammation; interleukin 1; laboratory mouse; microglia; neural degeneration; neuritic plaques; neurofibrillary tangles; neuropathology; neurotrophic factors; partial seizure; pathologic process; temporal lobe /cortex disorder

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的目的是解决这样的想法，即胶质细胞炎性变化与胶质细胞源性细胞因子，特别是白细胞介素-1（IL-1）和S100 β的过度表达，是导致阿尔茨海默病（AD）早期发病机制中神经元细胞损伤和死亡的级联事件中的引物。神经元功能障碍的这些胆碱驱动的级联包括β APP的早期过表达、神经元缠结的积累、β APP过表达神经突的过度生长、神经纤维丝的出现以及最终的细胞死亡。这些神经递质驱动的神经退行性级联反应的慢性激活反过来可以促进IL-1的进一步过度表达。以这种方式，这些细胞因子驱动的级联可以变成自我繁殖，如“细胞因子循环”中所示。为了阐明该循环的各个方面，我们将使用分子技术来：1）定义阿尔茨海默病中神经胶质炎症与神经元细胞损伤（如通过β APP过表达和神经元、神经突和神经纤维丝中的神经纤维缠结形成以及通过突触变化所证明的）和神经元细胞死亡（如通过TUNEL阳性所证明的）的关系。这些将与以下发生率相关：i）相关的活化小胶质细胞过度表达IL-1）; ii）相关的活化小胶质细胞过度表达IL-1; ii）相关的活化星形胶质细胞过度表达S100 β; iii）相关的不同类型的β-淀粉样蛋白斑块;和iv）神经元缠结形成的阶段。2)定义在易患阿尔茨海默病或加速阿尔茨海默型衰老变化的条件下，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，我们将使用来自Braak和Braak阶段I-IV阿尔茨海默病相关变化的患者、唐氏综合征患者、头部损伤患者和癫痫患者的材料。3)在具有细胞因子周期元件表达改变的遗传动物模型中，检查改变的胶质细胞因子表达和神经元细胞损伤和死亡的程度和性质。其中包括betaAPP转基因小鼠和S100 beta转基因小鼠。4)使用含有特定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，评估外源性胶质细胞因子在体内的局部和远端效应。这些具体目标的成功完成将提供有关神经病理学变化进展的信息，并突出治疗策略的目标，以减缓阿尔茨海默病的临床进展。