Downstream Regulators B-amyloid Induced Neuronal Death

描述(由申请人提供)：我们的总体目标是确定 β-淀粉样蛋白诱导神经元死亡的分子机制。存放 不溶性Abeta，以及缠结形成和神经元丢失，是 阿尔茨海默氏症的特征。最近的研究表明，增加的Abeta 诱导突触毒性，这是一个与认知能力下降相关的参数 广告。我们的工作和其他实验室的证据表明，无法解决的 Abeta可诱导培养的神经细胞发生凋亡。Abeta介导的死亡途径 与营养因子剥夺(TFD)介导的死亡有许多相似之处 路径。其中包括c-fos和c-jun的诱导，细胞周期的使用 组分，JNK级联的激活，以及bcl2的保护。我们有 清楚地证明了caspase-2对于Abeta和TFD都是必需的 介导的死亡，尽管caspase-3有平行激活，但它 不足以导致死亡。然而，从caspase-2获得的数据为空 老鼠表明，这两种刺激的死亡途径并不相同： 这些小鼠培养的交感神经元受到Abeta的保护，但不受保护 来自TFD的。我们提出假设，Abeta和TFD都是通过一种 Caspase-2介导的途径，但caspase的相对表达 监管机构(IAP和Diablo/SMAC)确定不同的替代路径 Abeta和TFD。我们还提出了一个假设，即JNK激活导致 诱导Fas，募集RAIDD激活caspase-2。通过 对比和比较这两种死亡刺激使用的机制，我们 可以进一步剖析Abeta介导的死亡途径。我们将对这些进行研究 有以下具体目的的假设：1.确定哪些caspase是 在Abeta和TFD介导的死亡过程中被激活(处理)，以及哪些caspase 可以执行Abeta和TFD诱导的死亡。2.确定是否有 Abeta或TFD后MIAP3或DIABLO的差异表达及调控 3.确定JNK级联的激活是否导致caspase-2 激活。4.确定Abeta死亡的分子组成是否 在阿尔茨海默病小鼠模型中，在前面的目的中确定的途径被改变 和/或在人类阿尔茨海默病大脑中。

DESCRIPTION (provided by applicant): Our overall aim is to determine the molecular mechanisms of beta-amyloid-induced neuronal death. Deposition of insoluble Abeta, together with tangle formation and neuronal loss, are hallmarks of Alzheimer's disease. Recent studies show that increased Abeta induces synaptotoxicity, a parameter which correlates with cognitive decline in AD. Evidence from our work and from other laboratories shows that insoluble Abeta induces apoptosis in cultured neurons. The Abeta-mediated death pathway has many similarities to the trophic factor deprivation (TFD) mediated death pathway. These include induction of c-fos and c-jun, use of cell cycle components, activation of the JNK cascade, and protection by bcl-2. We have clearly demonstrated that caspase-2 is necessary for Abeta as well as for TFD mediated death and that although there is parallel activation of caspase-3 it is not sufficient to induce death. However, data obtained from caspase-2 null mice indicate that the death pathways of these two stimuli are not identical: cultured sympathetic neurons from these mice are protected from Abeta but not from TFD. We propose the hypothesis that Abeta and TFD both execute death via a caspase-2 mediated pathway but that the relative expression of caspase regulators (IAPs and Diablo/SMAC) determines different alternative pathways for Abeta and TFD. We additionally propose the hypothesis that JNK activation leads to induction of Fas and recruitment of RAIDD activating caspase-2. By contrasting and comparing the mechanisms employed by these two death stimuli we can further dissect the Abeta-mediated death pathway. We will examine these hypotheses with the following specific aims: 1. To determine which caspases are activated (processed) during Abeta and TFD mediated death and which caspases can execute Abeta and TFD induced death. 2. To determine whether there is differential expression and regulation of MIAP3 or Diablo after Abeta or TFD. 3. To determine whether activation of the JNK cascade leads to caspase-2 activation. 4. To determine whether the molecular components of the Abeta death pathway, identified in the preceding Aims, are altered in a mouse model of AD and/or in human AD brain.