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: 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
• 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
• 来源: https://reporter.nih.gov/project-details/6098591
• 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的目标是解决这一观点，即在阿尔茨海默病(AD)的早期发病机制中，胶质细胞炎性变化与胶质细胞衍生细胞因子，特别是白细胞介素1(IL-1)和S100β的过度表达是导致神经细胞损伤和死亡的一系列事件的启动因素。这些细胞因子驱动的神经元功能障碍包括早期βAPP的过度表达，神经原纤维缠结的积累，βAPP过度表达的神经突起的过度生长，神经纤维束的出现，最终细胞死亡。这些细胞因子驱动的神经退行性级联的慢性激活可以反过来促进IL-1的进一步过度表达。通过这种方式，这些由细胞因子驱动的级联可能会变得自我传播，如“细胞因子循环”所示。为了阐明这一周期的各个方面，我们将使用分子技术来：1)确定阿尔茨海默病患者胶质细胞炎症与神经细胞损伤(表现为神经元、轴突和神经纤维束中的βAPP过度表达和神经纤维缠结形成，以及突触变化)和神经细胞死亡(表现为TUNEL阳性)之间的关系。这些将与：i)相关的激活的小胶质细胞过度表达IL-I；ii)相关的激活的小胶质细胞过度表达IL-1；ii)相关的激活的星形胶质细胞过度表达S100β；iii)相关的不同类型的β-淀粉样斑块；以及iv)神经纤维缠结形成的阶段。2)确定在易患阿尔茨海默病或加速阿尔茨海默型老年性改变的情况下，胶质细胞炎症与神经细胞损伤和死亡的时间和空间关系。为此，我们将使用来自阿尔茨海默病相关变化的Braak和Braak分期I-IV的患者、唐氏综合症、头部损伤和癫痫患者的材料。3)检测细胞因子周期元件表达改变的遗传性动物模型中胶质细胞因子表达改变的程度和性质以及神经细胞损伤和死亡的程度和性质。其中包括BetaAPP转基因小鼠和S100β转基因小鼠。4)通过脑内植入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微丸，评估外源性胶质细胞因子在体内的局部和远程影响。这些特定目标的成功完成将提供有关神经病理变化进展的信息，并突出治疗战略的目标，以减缓阿尔茨海默病的临床进展。