C-JUN AND AMYLOID-INDUCED APOPTOSIS

描述：细胞凋亡是细胞死亡的一种类型， 在正常情况下导致神经元丢失的特征形态 在发展和病理情况下，包括阿尔茨海默病(AD)， 亨廷顿病、中风和癫痫。尽管越来越多的人对 过程中，关于神经元分子机制的细节很少 细胞凋亡是已知的。我们之前发现了一个时间级联的基因 神经诱导交感神经元凋亡的实验研究 剥夺了生长因子(NGF)并显示出蛋白质产物中的一种 诱导基因c-jun是死亡所必需的。在皮质神经元中， 阿尔茨海默病淀粉样蛋白b诱导的细胞凋亡 与之前发现的惊人相似的遗传级联， 包括健壮的c-jun诱导。由于(I)c-jun mRNA是在 单抗处理或NGF剥夺引起的神经细胞凋亡(II) 这一c-jun基因在两种模型中似乎都能形成具有功能的c-jun蛋白。 系统，通过随后“下游”基因的激活而被识别， 和(Iii)c-jun是NGF剥夺后细胞凋亡所必需的，我们的 目前的工作假说是，导致、调节和 包括c-jun的诱导是抗体诱导神经元死亡所必需的。 为了追求这一假设，我们建议(I)比较和对比 神经细胞凋亡过程中基因表达的变化 AB-NGF剥夺的治疗；(Ii)确定c-Jun在抗体中的作用 显微注射中和抗体诱导神经细胞凋亡 和显性否定形式c-jun的异位表达；(Iii)阐明 单抗诱导神经元c-jun基因表达的机制(S) 特别强调氧化应激的作用；(4)探讨可能的 C-jun作用机制的初步研究 细胞周期重入，包括c-jun异二聚体的形成模式；(V) 神经细胞凋亡与“凋亡”基因表达模式的比较 并控制脑组织以辨别这种遗传级联反应是否可能 在活体内导致神经元丢失。 这些研究将评估抗体诱导神经元死亡的假说 严重依赖于基因表达的改变，即氧化应激 这些遗传事件的中心，并且这种遗传级联可能 导致AD患者体内神经元丢失。因此，这项工作将进一步 我们的长期目标是阐明神经元死亡的机制， 最终，确定预防这种死亡的药理方法。

DESCRIPTION: Apoptosis is emerging as a type of cell death with characteristic morphology that contributes to neuronal loss during normal development and in pathologic situations, including Alzheimer disease (AD), Huntington disease, stroke and seizure. Despite increasing interest in the process, few details concerning the molecular mechanisms of neuronal apoptosis are known. We previously identified a temporal cascade of gene induction in sympathetic neurons undergoing apoptosis because of nerve growth factor (NGF) deprivation and showed that the protein product of one induced gene, c-Jun, was necessary for death. In cortical neurons, apoptosis induced by AD amyloid b-protein (Ab) treatment is accompanied by a genetic cascade that is strikingly similar to that identified previously, including a robust c-jun induction. Since (i) c-jun mRNA is induced during neuronal apoptosis initiated by either Ab-treatment or NGF deprivation, (ii) this c-jun mRNA appears to form functional c-Jun protein in both model systems, as discerned by the subsequent activation of "downstream" genes, and (iii) c-Jun is necessary for apoptosis after NGF deprivation, our current working hypothesis is that events which lead up to, modulate, and include the induction of c-jun are necessary for Ab-induced neuronal death. In pursuit of this hypothesis, we propose to (i) compare and contrast patterns of gene expression in neurons undergoing apoptosis as a result of Ab -treatment of NGF-deprivation; (ii) define the role of c-Jun in Ab -induced neuronal apoptosis by using microinjected, neutralizing antibodies and ectopic expression of a dominant negative form of c-Jun; (iii) elucidate the mechanism(s) leading to c-jun induction in Ab-treated neurons, with particular emphasis on the role of oxidative stress; (iv) explore a possible mechanism of c-Jun action by analyzing Ab -treated neurons for markers of cell cycle re-entry, including patterns of c-Jun heterodimer formation; (v) compare the patterns of neuronal apoptosis and "apoptotic" gene expression in AD and control brain tissue to discern whether this genetic cascade may contribute to neuronal loss in vivo. These studies will evaluate the hypotheses that Ab -induced neuronal death is critically dependent on altered gene expression, that oxidative stress is central to these genetic events, and that this genetic cascade may contribute to neuronal loss in vivo in AD. Hence, this work will further our long-term goals of elucidating the mechanisms underlying neuronal death, and, ultimately, identifying pharmacologic means to prevent this death.