CYTOKINES, NEURODEGENERATION AND DOWN'S SYNDROME

细胞因子、神经变性和唐氏综合症

• 批准号: 6521224
• 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 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6521224
• 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.

本提案的目的是研究，在人类和实验范例，由21号染色体基因产物的过度表达的存在所产生的事件序列，这些基因产物引起阿尔茨海默型神经退行性变化和认知能力下降，这些变化和认知能力下降是唐氏症患者中年的特征。 我们提出，21三体基因加载直接促进β-淀粉样前体蛋白（betaAPP）的合成及其分泌片段（sAPP）的释放，进而激活小胶质细胞并诱导白细胞介素-1（IL-1）（主要促炎细胞因子）的合成和释放。 我们进一步提出，正是通过这种细胞因子的作用，神经退行性事件通过我们称之为细胞因子周期的自传播级联反应得以延续。 例如，IL-1（i）上调β-淀粉样前体蛋白（β APP）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;和（ii）诱导星形胶质细胞中S100 β的合成和释放。 这些IL-1介导的事件通过AchE诱导的阿尔茨海默病和唐氏病相关神经递质乙酰胆碱的降解以及通过S100 β诱导的细胞死亡（通过神经元钙的增加、β APP的过度合成和神经突的不适当生长）而增加神经元功能障碍的可能性。 我们假设，鉴于IL-1为基础的行动和潜在的慢性IL-1过度表达唐氏直接和间接促进神经元损伤和死亡，阿尔茨海默氏症型的变化的进展是由细胞因子周期中的自我传播事件驱动。 我们将确定唐氏综合征和部分16三体动物模型中细胞因子周期元素与神经元细胞损伤和死亡之间的时间和空间关系。 将使用用于递送细胞因子周期元素和适当阻断剂以及细胞共培养系统模型的植入范例来定义负责这些关系的机制。我们目标的实现将阐明唐氏症患者中年时认知功能明显下降的致病机制，并为可能的治疗干预提供靶点。