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。沉积 不溶性Abeta与缠结形成和神经元损失一起， 老年痴呆症的特征最近的研究表明， 诱导突触毒性，这是一个与认知能力下降相关的参数， AD.我们的工作和其他实验室的证据表明， Abeta在培养的神经元中诱导凋亡。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 通路这些包括c-fos和c-jun的诱导， JNK级联的激活和bcl-2的保护。我们有 明确表明caspase-2是Abeta和TFD所必需的， 介导的死亡，尽管存在caspase-3的平行激活， 不足以导致死亡。然而，从caspase-2获得的数据无效， 小鼠表明这两种刺激的死亡途径并不相同： 来自这些小鼠的培养的交感神经元被保护免受Abeta的侵害， 从TFD。我们提出假设，Abeta和TFD都是通过一个 caspase-2介导的途径，但caspase的相对表达 监管机构（IAP和Diablo/SMAC）确定不同的替代途径， Abeta和TFD。我们还提出假设，JNK激活导致 诱导Fas和募集RAIDD激活caspase-2。通过 对比和比较这两种死亡刺激的机制， 可以进一步剖析Abeta介导的死亡途径。我们将研究这些 具有以下具体目标的假设：1。为了确定哪些半胱天冬酶 在Abeta和TFD介导的死亡过程中激活（加工）， 可以执行Abeta和TFD诱导的死亡。2.以确定是否存在 在Abeta或TFD之后，MIAP 3或Diablo的差异表达和调节。 3.为了确定JNK级联反应的激活是否导致caspase-2 activation. 4.为了确定Abeta死亡的分子组成 在AD小鼠模型中， 和/或在人AD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.