INJURY RESPONSES IN ALZHEIMER DISEASE AND OTHER HUMAN CONDITIONS

项目一的目标是解决过度表达的想法 胶质细胞来源的细胞因子，特别是白介素1(IL-1)，是一种 阿尔茨海默病(AD)发病机制中的事件，导致 导致神经元的细胞和分子事件的双臂级联 细胞功能障碍，包括神经原纤维缠结和 神经突起过度生长，最终导致死亡，导致进一步 IL-1在后来成为自我传播的“系统”中的过度表达 或者是瀑布。 在AD中，我们寻找与级联相关的细胞参与的证据 以及在假定的神经病理进展中的分子事件 痴呆进行性的解释是通过确定他们的 与以下方面的相互关系：(I)特定斑块类型和(Ii) 公认阿尔茨海默病神经病变的区域分布。 在头部损伤中，这是最近确定的未来发展的危险因素 对于AD，我们可以知道发病的时间和年龄、严重程度和临床 从而将这些参数与斑块的分布联系起来 根据大脑区域内和不同区域的类型。 在非痴呆性重症冠状动脉疾病(CCAD)患者中 观察到明显的AD样神经病变，我们寻求 为了澄清这些变化与AD的关系，我们：(I)比较 它们的区域分布与AD的分布和(Ii)评估潜力 与级联相关的细胞和分子事件在特定情况下的参与 大脑区域内和跨大脑区域的斑块类型。 在难治性颞叶癫痫中，我们有证据表明 发生与级联相关的细胞和分子事件时，我们寻求：(I) 评估明确的致痫灶和致痫灶之间的空间关系 这些事件和(二)将这些事件与AD发生的事件进行比较，Head 受伤，和CCAD。 我们实验室将使用一些常规的分子技术 以实现我们的具体目标，在成功完成后将提供 关于我们建议的级联的概括性的信息--a 如果它对开发合理的治疗方法有用，那么它是必要的 战略。

The objective of Project One is to address the idea that overexpression of glia-derived cytokines, especially interleukin-1 (IL-1), is a seminal event in the pathogenesis of Alzheimer's disease (AD), giving rise to a two-armed cascade of cellular and molecular events that lead to neuron cell dysfunctions, including accumulation of neurofibrillary tangles and overgrowth of neurites, and eventually death which induces further overexpression of IL-1 in what becomes then a self-propagating "system" or cascade. In AD, we seek evidence of the involvement of cascade-related cellular and molecular events in the presumed neuropathological progression that accounts for the progressive nature of the dementia by determining their interrelationships with regard to: (i) specific plaque types and (ii) the recognized regional distribution of neuropathological changes in AD. In head injury, a recently established risk factor for later development of AD, we can know the time and age at onset, severity, and clinical course and thus relate these parameters to the distribution of plaques according to type within as well as across brain regions. In non-demented critical coronary artery disease (cCAD) patients where significant AD-like neuropathological changes have been observed, we seek to clarify the relationship of these changes to AD as we: (i) compare their regional distribution to that in AD and (ii) assess the potential involvement of cascade-related cellular and molecular events in specific plaque types within and across brain regions. In refractory temporal epilepsy, where we have evidence that some cascade-related cellular and molecular events occur, we seek to: (i) evaluate spatial relationships between defined epileptogenic foci and these events and (ii) compare these with those occurring in AD, head injury, and cCAD. A number of molecular techniques routine to our laboratory will be used to address our specific aims, which at successful completion will provide information regarding the generalizability of our proposed cascade--a necessity if it is to be useful in developing rational therapeutic strategies.