GLIAL NEURONAL INTERACTION IN ALZHEIMERS DISEASE

项目1的目标是解决神经胶质炎性变化与神经胶质源性细胞因子的过度表达，特别是白细胞介素-1 （IL-1）和s100 β，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一系列事件的引物推动者。这些细胞因子驱动的神经元功能障碍级联反应包括早期betaAPP的过度表达、神经原纤维缠结的积累、betaAPP-过度表达的神经突的过度生长、神经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可进一步促进IL-1的过度表达。通过这种方式，这些细胞因子驱动的级联可能会自我繁殖，如“细胞因子周期”所示。为了阐明这一循环的各个方面，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（通过神经元、神经突和神经丝线中β - app过表达和神经原纤维缠结形成以及突触改变来证明）和神经元细胞死亡（通过TUNEL阳性来证明）的关系。这些将与以下情况的发生率相关：i)相关的活化小胶质细胞过表达IL-i；ii)相关激活的小胶质细胞过度表达IL-1；ii)相关活化星形胶质细胞过表达s100 β；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)明确易患阿尔茨海默病或加速阿尔茨海默型衰老变化条件下神经胶质炎症与神经元细胞损伤和死亡的时空关系。为此，我们将使用来自阿尔茨海默病相关变化的Braak和Braak I-IV期患者、唐氏综合症患者、头部损伤患者和癫痫患者的资料。3)在细胞因子周期元件表达改变的遗传动物模型中，研究胶质细胞因子表达改变的程度和性质以及神经元细胞损伤和死亡。其中包括betaAPP转基因小鼠和s100 β转基因小鼠。4)通过脑内植入含有特异性胶质细胞因子和其他细胞因子周期分子的缓释微球，评估外源性胶质细胞因子在体内的局部和远程效应。成功完成这些特定目标将提供有关神经病理变化进展的信息，并突出治疗策略的目标，以减缓阿尔茨海默病的临床进展。

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.