CYTOKINES, NEURODEGENERATION AND DOWN'S SYNDROME

本提案的目的是研究，在人类和实验范式中，由21号染色体基因产物过度代表的存在所产生的事件序列，导致阿尔茨海默型神经退行性变化和认知能力下降，这是唐氏病患者中年的特征。我们提出21三体基因负载直接促进β -淀粉样蛋白前体蛋白（betaAPP）的合成和其分泌片段（sAPP）的释放，进而激活小胶质细胞并诱导主要促炎细胞因子白介素-1 （IL-1）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为细胞因子周期的自我传播级联而持续存在。例如，IL-1 (i)上调神经元中β -淀粉样蛋白前体蛋白（betaAPP）的表达和加工以及乙酰胆碱酯酶（AchE）的活性和mRNA水平；（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s100 β通过神经元钙增加、β app过度合成和神经突不适当生长诱导的细胞死亡，增加了神经元功能障碍的可能性。鉴于IL-1的作用和慢性IL-1过表达在唐氏症中直接或间接促进神经元损伤和死亡的潜力，我们假设，阿尔茨海默病型变化的进展是由细胞因子周期中的自我传播事件驱动的。我们将在唐氏综合症和部分三体16动物模型中确定细胞因子周期元素与神经元细胞损伤和死亡之间的时空关系。细胞因子周期元件和适当阻滞剂的植入模式以及细胞共培养系统模型将用于定义负责这些关系的机制。完成我们的目标将阐明唐氏病患者中年认知能力明显下降的致病机制，并为可能的治疗干预提供目标。

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.