EARLY EVENTS IN ALZHEIMER PATHOGENESIS

这个项目的目的是批判性地评估一个假设的细胞因子周期的分子和细胞事件，我们提出的是重要的阿尔茨海默病的发病机制。在这个周期中，研究了效应子刺激的小胶质细胞活化，合成和释放胶质细胞炎性细胞因子白细胞介素-1（IL-1）。基于IL- 1的作用包括（i）诱导β-淀粉样前体蛋白（β APP）在神经元中的过度表达和加工（导致β-淀粉样蛋白沉积、细胞死亡和分泌的APP的释放，刺激IL-1的进一步表达）;和（ii）星形胶质细胞的活化和S100 β的释放（通过促进神经元内钙的增加，通过促进β-APP的合成，以及通过诱导营养不良神经突的过度生长）以及合成和释放ApoE（其可以结合β-淀粉样蛋白并使其稳定）。阿尔茨海默氏病本质上是进行性的，任何被假设为显著有助于这种疾病发病机制的事件序列都必须解释这种进展。并且任何被假设为对该疾病的发病机制有显著贡献的事件序列都必须解释该进展。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，以促进神经元损伤和死亡，阿尔茨海默氏病的进展可能是由这种潜在的自我传播，自我维持的序列事件。我们将确定神经胶质炎症过程在阿尔茨海默病和癫痫中神经元细胞损伤和死亡中的作用，这容易导致早期阿尔茨海默型变化。我们还将确定唐氏综合征和脑损伤后神经胶质炎症过程与神经元细胞损伤和死亡之间的时空关系，以及基因型对这些过程的调节作用。我们还将使用过表达S100 β或β APP的转基因动物来定义这些关系的机制。细胞培养模型将用于确定神经胶质炎性蛋白调节神经元细胞损伤和死亡的机制。该计划目标的实现将产生直接有益于确定阿尔茨海默病发病机制基本要素的结果，并为制定治疗策略提供目标。

The objective of this Program Project is to critically evaluate a hypothesized cytokine cycle of molecular and cellular events that we propose is important in the pathogenesis of Alzheimer disease. Effector- stimulated microglial activation with synthesis and release of the glial inflammatory cytokine interleukin-1 (IL-1) is seminar in this cycle. IL- 1-based actions include (i) induction of over-expression and processing of beta-amyloid precursor protein (betaAPP) in neurons (leading to beta- amyloid deposition, cell death and release of secreted APP, stimulating further expression of IL-1); and (ii) activation of astrocytes and release of S100beta (increasing the potential for cell death by promoting increases in intraneuronal calcium, by promoting synthesis of beta-APP, and by inducing overgrowth of dystrophic neurites) and with synthesis and release of ApoE (which may bind to beta-amyloid and stabilize it). Alzheimer's disease is inherently progressive, and any sequence of events hypothesized to significantly contribute to the pathogenesis of this disease must explain this progression., and any sequence of events hypothesized to significantly contribute to the pathogenesis of this disease must explain this progression. We postulate, in view of IL-1 based actions, and the potential of chronic IL-1 over-expression to promote neuronal injury and death, that the progression of Alzheimer's disease may be driven by this potentially self propagating, self sustaining sequence events. We will determine the role of glial inflammatory processes in neuronal cell injury and death in Alzheimer's disease and in epilepsy, which predisposes to early Alzheimer-type changes. We will also determine temporal and spatial relationships between glial inflammatory processes and neuronal cell injury and death in Down's syndrome and following head injury, and the modulating effects of genotype on these processes. We will also use transgenic animals over-expressing S100beta or betaAPP to define mechanisms responsible for these relationships. Cell culture models will be used to define mechanisms by which glial inflammatory proteins modulate neuronal cell injury and death. Accomplishment of the goals of this Program will yield results of direct benefit to the identification of basic elements in Alzheimer pathogenesis and provide targets for development of therapeutic strategies.