Early Events in Alzheimer Pathogenesis

该项目将严格评估假设的分子和细胞事件的“细胞因子周期”，该周期在阿尔茨海默病（AD）和其他以神经胶质活化和白细胞介素-1 （IL-1）的过度表达为特征的退行性疾病的发病机制中很重要。神经损伤是由创伤、遗传和衰老等效应引起的，导致IL-1的过度表达，从而导致进一步的退化。IL-1的过度表达导致(i)诱导神经元过度表达和β -淀粉样蛋白前体蛋白（betaAPP）的加工，导致β沉积、细胞死亡和分泌的APP的释放，每一个都刺激IL-1的进一步过度表达；（ii）通过s100 β的合成和释放激活星形胶质细胞，通过促进神经元内钙的增加、促进β - app的合成和诱导营养不良神经突的过度生长来增加细胞死亡的可能性。我们将确定IL-1基因型在阿尔茨海默病和可能易患阿尔茨海默病病理（如早期Braak和Braak阶段、癫痫和头部损伤）的神经胶质炎症过程和神经元细胞损伤和丢失中的作用。我们还将研究IL-1驱动的级联在肌肉中促进修复和退行性过程的可能性，其中包括增加β - app的表达和其他与神经退行性变相似的细胞因子周期。此外，我们将研究IL-1基因型在老年受试者中观察到的肌肉适应损伤性运动的变异性的可能性。转基因动物，过度表达或不表达s100 β或IL-1或携带人类突变的betaAPP或这些基因型的组合，将用于定义负责上述神经退行性变的机制，并定义在肌肉衰老过程中由这些遗传变异引起的机制。细胞培养模型将用于确定炎症蛋白介导和传播兴奋毒性神经元细胞损伤和运动诱导的肌肉细胞损伤和死亡的机制，并探索潜在或假定的治疗药物的改善作用。完成本项目的目标将产生结果，直接确定阿尔茨海默病发病机制的基本机制，并为开发退行性疾病的治疗策略提供目标。

This Program Project will critically evaluate a hypothesized "cytokine cycle" of molecular and cellular events that is important in the pathogenesis of Alzheimer's disease (AD) and other degenerative conditions that are characterized by glial activation and over-expression of interleukin-1 (IL-1). Neuronal injury, induced by effectors such as trauma, genetics, and aging, results in over-expression of IL-1, which has known leads to further degeneration. IL-1 over-expression results in (i) induction of neuronal over-expression and processing of beta-amyloid precursor protein (betaAPP), leading to Abeta deposition, cell death, and release of secreted APP, each stimulating further over-expression of IL-1); and (ii) activation of astrocytes with synthesis and release of S100beta, increasing the potential for cell death by promoting increases in intraneuronal calcium, promoting synthesis of betaAPP, and inducing over-growth of dy6strophic neurites. We will determine the role of IL-1 genotype in glial inflammatory processes and neuronal cell injury and loss in AD and in conditions that may predispose to AD pathology, e.g., early Braak and Braak stages, epilepsy, and head injury. We will also investigate the possibility that IL-1 driven cascades in muscle contribute to repair and degenerative processes, which include increase expression of betaAPP and other cytokine cycle parallels to neurodegeneration. Moreover, we will investigate the possibility that IL-1 genotype contributes to the variability in muscle adaptation to damaging exercise observed in older subjects. Transgenic animals, over- or not expressing S100beta or IL-1 or carrying human mutated betaAPP or combinations of these genotypes, will be used to define mechanisms responsible for neurodegeneration described above, and to define mechanisms evoked by these genetic variations during aging in muscle. Cell culture models will be used to define mechanisms by which inflammatory proteins may mediate and propagate excitotoxic neuronal cell injury and exercise-induced muscle cell injury and death, and to explore the ameliorating effect of potential or putative therapeutic agents. Accomplishment of the goals of this Program Project will yield results that directly identify basic mechanisms in Alzheimer pathogenesis and provide targets for developing therapeutic strategies for degenerative conditions in general.