Cell cycle events: outcomes measures in Alzheimer models

描述（由申请人提供）：阿尔茨海默病（AD）是一种神经退行性疾病，仅在美国就影响了近400万人。近年来，对阿尔茨海默病（AD）的遗传学、生物化学和病理学的了解有所进展，但神经变性的生物学仍然是一个谜。已经开发了几种AD小鼠模型。这些近乎完美的“种族灭绝”再现了阿尔茨海默病的一些病理特征，但它们是不完美的“表型”。除此之外，它们不能复制神经元细胞死亡的表型。我们的实验室和其他人已经证明，在人类AD大脑中有死亡风险的人群中，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，并且是观察到的人类疾病中神经退行性变的近端原因。定量分析显示细胞周期事件（CCEs）证据的神经元数量预测缓慢死亡，需要数月。我们现在有初步的证据表明，尽管没有神经细胞死亡，但小鼠模型确实在适当的人群中启动了神经细胞周期。这种疾病通过不同大脑区域的进展模拟了人类的情况，值得注意的是，3个月的适当时间的非甾体抗炎药治疗可以阻止CCEs的出现。在这个修改后的申请中，我们建议完成我们对4种不同AD小鼠模型中CCEs的自然历史的描述，并将它们与其他病理疾病标志物（淀粉样蛋白沉积，活化的小胶质细胞等）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“第二次打击”的功效，以驱动循环神经元死亡。其次，我们将测试CCEs对目前正在探索用于治疗阿尔茨海默病的非甾体抗炎药的反应：布洛芬、辛伐他汀和一种新的方法GW3965，一种LXR受体激动剂。我们将在CCEs首次出现之前和之后开始治疗，使用不同的APR转基因以及遗传背景作为变量。CCEs作为临床前阿尔茨海默病试验中使用的一种新的结局指标的潜在价值是5倍：它们易于检测；它们是神经元表型；它们与神经元细胞死亡有概念上的联系；它们在老鼠和人身上都有；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.