Early Events in Alzheimer Pathogenesis

该项目将严格评估一个假设的“细胞因子周期”的分子和细胞事件，这是重要的阿尔茨海默病（AD）和其他退行性疾病的发病机制，其特征是神经胶质细胞活化和过度表达的白细胞介素-1（IL-1）。由诸如创伤、遗传学和衰老等效应物诱导的神经元损伤导致IL-1的过度表达，这已知导致进一步变性。IL-1过表达导致（i）诱导神经元过表达和β-淀粉样前体蛋白（β APP）的加工，导致A β沉积、细胞死亡和分泌的APP的释放，每种都刺激IL-1的进一步过表达）;和（ii）通过合成和释放S100 β激活星形胶质细胞，通过促进神经元内钙的增加而增加细胞死亡的可能性，促进β APP的合成，诱导营养不良神经突的过度生长。我们将确定IL-1基因型在AD中的神经胶质炎症过程和神经元细胞损伤和损失中的作用，以及在可能易患AD病理学的条件下，例如，早期Braak和Braak分期癫痫和头部损伤我们还将研究肌肉中IL-1驱动的级联反应有助于修复和退行性过程的可能性，其中包括β APP和其他与神经退行性相关的细胞因子周期的表达增加。此外，我们将调查IL-1基因型有助于在老年受试者中观察到的肌肉适应损伤运动的变异性的可能性。过度表达或不表达S100 β或IL-1或携带人突变β APP或这些基因型的组合的转基因动物将用于定义负责上述神经变性的机制，并定义在肌肉老化期间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性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，并探索潜在或推定的治疗剂的改善作用。该计划项目目标的实现将产生直接识别阿尔茨海默病发病机制的基本机制的结果，并为一般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.