CYTOKINES, NEURODEGENERATION AND DOWN'S SYNDROME

细胞因子、神经变性和唐氏综合症

• 批准号: 6786751
• 负责人: Sue Tilton Griffin
• 金额: $ 24.7万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6786751
• 关键词: Downs syndrome; amyloid proteins; apolipoprotein E; cognition disorders; cytokine; enzyme linked immunosorbent assay; gel mobility shift assay; gene expression; genetic polymorphism; genotype; human tissue; immunocytochemistry; in situ hybridization; interleukin 1; laboratory mouse; mixed tissue /cell culture; neural degeneration; neuritic plaques; neurofibrillary tangles; neurons; neuropathology; northern blottings; polymerase chain reaction; trisomy; ultraviolet spectrometry; western blottings

The objective of this proposal is to study, in human and experimental paradigms, the sequence of events engendered by the presence of over representation of chromosome 21 gene products that give rise to the Alzheimer-type neurodegenerative changes and cognitive decline that are characteristic of middle age in Down's patients. We propose that trisomy 21 gene loading directly promotes synthesis of beta-amyloid precursor protein (betaAPP) and release of its secreted fragments (sAPP) that, in turn, activates microglia and induces synthesis and release of interleukin-1 (IL-1) the principle proinflammatory cytokine. We further propose that it is through the actions of this cytokine that neurodegenerative events are perpetuated via a self propagating cascade that we termed the cytokine cycle. For example, IL-1 (i) upregulates the expression and processing of beta-amyloid precursor protein (betaAPP) and the activity and mRNA levels of acetyl cholinesterase (AchE) in neurons; and (ii) induces synthesis and release of S100beta in astrocytes. These IL-1 mediated events increase the potential for neuronal dysfunction by AchE-induced degradation of the Alzheimer's and Down's related neurotransmitter acetyl choline, as well as by S100beta-induced cell death through increases in neuronal calcium, excessive synthesis of betaAPP, and inappropriate growth of neurites. We postulate, in view of IL-1 based actions and the potential of chronic IL-1 overexpression in Down's to directly and indirectly promote neuronal injury and death, that the progression of Alzheimer-type changes are driven by self propagating events in the cytokine cycle. We will determine temporal and spatial relationships between cytokine cycle elements and neuronal cell injury and death in Down's syndrome and in partial trisomy 16 animal models. An implantation paradigm for delivering cytokine cycle elements and appropriate blockers together with cell co-culture system models will be used to define mechanisms responsible for these relationships. Accomplishment of our aims will elucidate the pathogenic mechanisms underlying the cognitive decline apparent at middle age in Down's patients and provide targets for possible therapeutic intervention.

该提案的目的是在人类和实验范式中研究由21个基因产物的过度表示产生的事件的顺序，这些事件导致阿尔茨海默氏症型神经退行性变化和认知下降，这些变化和认知下降是中年患者中年患者的特征。 我们提出，三体性21基因载荷直接促进β-淀粉样蛋白前体蛋白（betaApp）的合成及其分泌片段（SAPP）的释放，从而激活了小胶质细胞并诱导白介素1（IL-1）的合成和释放。 我们进一步建议，通过这种细胞因子的作用，神经退行性事件通过自我传播的级联反应而持续，我们称我们称为细胞因子循环。 例如，IL-1（i）上调β-淀粉样蛋白前体蛋白（betaApp）的表达和加工以及神经元中乙酰胆碱酯酶（ACHE）的活性和mRNA水平； （ii）在星形胶质细胞中诱导S100beta的合成和释放。 这些IL-1介导的事件通过ACHE诱导的阿尔茨海默氏症和唐的相关神经递质乙酰胆碱的降解以及S100BETA诱导的细胞死亡而导致神经元功能障碍的可能性，从而增加了神经元的功能障碍。 鉴于基于IL-1的作用，我们假设Down的慢性IL-1过表达的潜力直接和间接地促进神经元损伤和死亡，因此，阿尔茨海默氏症型变化的进展是由细胞因子循环中自我传播的事件驱动的。 我们将确定唐氏综合症的细胞因子循环元素与神经元细胞损伤与死亡之间的时间和空间关系，以及在部分三体性动物模型中。 用于传递细胞因子循环元素和适当阻滞剂以及细胞共培养系统模型的植入范式将用于定义负责这些关系的机制。我们的目标的实现将阐明唐斯患者中期认知下降的基础的致病机制，并为可能的治疗干预提供了靶标。