Cell cycle events: outcomes measures in Alzheimer models

描述(申请人提供)：阿尔茨海默病(AD)是一种神经退行性疾病，仅在美国就有近400万人受到影响。近年来，对阿尔茨海默病(AD)的遗传学、生化和病理学的了解有所进展，但神经退行性变的生物学仍是一个谜。已经开发了几种AD小鼠模型。这些近乎完美的‘基因复制’复制了阿尔茨海默病的一些病理特征，但它们是不完美的‘表象复制’。除此之外，它们不能复制神经细胞死亡的表型。我们的实验室和其他实验室已经表明，人类AD大脑中面临死亡风险的人群中的神经元提供了重新进入细胞周期的证据。我们提出，这种有丝分裂的尝试对神经元是致命的，是人类疾病中观察到的神经变性的近端原因。对显示细胞周期事件(CCES)证据的神经元数量的定量分析预测缓慢死亡，需要数月时间。我们现在有初步证据表明，尽管没有神经细胞死亡，小鼠模型确实在适当的人群中启动了神经细胞周期。疾病通过不同大脑区域的发展模拟了人类的情况，值得注意的是，适当时机的3个月非甾体抗炎药疗程阻止了CCES的出现。在这份修订的申请中，我们建议完成我们对4种不同AD小鼠模型的CCES的自然历史的描述，并将它们与其他病理疾病标记物(淀粉样沉积、激活的小胶质细胞等)联系起来。作为这一目标的一部分，我们将测试缺氧和免疫挑战作为驱动循环神经元死亡的“二次打击”的有效性。其次，我们将测试CCE对目前正在探索用于治疗阿尔茨海默病的非类固醇激素疗法的反应，这些疗法包括布洛芬、辛伐他汀和一种新方法，即LXR受体激动剂GW3965。我们将使用不同的APR转基因和遗传背景作为变量，在首次出现CCES之前和之后开始治疗。CCES作为一种新的结果指标用于临床前AD试验的潜在价值是5倍：它们易于检测；它们是一种神经细胞表型；它们与神经细胞死亡有概念上的联系；它们在小鼠和人类中都有发现；它们出现在病程的早期。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative illness that affects nearly 4 million individuals in the USA alone. Understanding of the genetics, biochemistry and pathology of Alzheimer's disease (AD) has advanced in recent years, but the biology of the neurodegeneration remains a mystery. Several AD mouse models have been developed. These near perfect 'genocopies' reproduce some of the pathological features of Alzheimer's disease, but they are imperfect 'phenocopies'. Among other things, they fail to reproduce the phenotype of neuronal cell death. Our lab and others have shown that neurons in populations at-risk for death in the human AD brain present evidence for re-entrance into a cell cycle. We have proposed that this attempt at mitosis is lethal for a neuron and is the proximal cause of the observed neurodegeneration in the human disease. Quantitative analysis of the number of neurons manifesting evidence of cell cycle events (CCEs) predicts a slow death, requiring many months. We now have preliminary evidence that despite the absence of nerve cell death the mouse models do initiate neuronal cell cycles in the appropriate populations. The progression of the disease through the various brain regions mimics the human condition and, significantly, a properly timed 3-month course of NSAID treatment blocks the appearance of the CCEs. In this revised application we propose to complete our description the natural history of the CCEs in 4 different AD mouse models, and to relate them to the other pathological disease markers (amyloid deposition, activated microglia etc.). As part of this aim we will test both hypoxia and immune challenge for their efficacy as a 'second hit' that drives the cycling neurons to die. Second, we will test the response of the CCEs to NSAIDS therapies that are currently being explored for use in the treatment of Alzheimer's disease: ibuprofen, simvastatin and an new approach, GW3965, an agonist of the LXR receptor. We will initiate therapy both before and after the first appearance of the CCEs using different APR transgenes as well as genetic background as variables. The potential value of CCEs as a new outcome measure for use in preclinical AD trials is 5-fold: they are easy to detect; they are a neuronal phenotype; they have a conceptual link to neuronal cell death; they are found in both mouse and man; and they appear early in the disease course.