Cell cycle events: outcomes measures in Alzheimer models

细胞周期事件：阿尔茨海默病模型的结果测量

• 批准号: 7103051
• 负责人: KARL HERRUP
• 金额: $ 34.23万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7103051
• 关键词: Alzheimer' s disease; amyloidosis; biomarker; cell cycle; cell population study; cellular pathology; chemoprevention; cytogenetics; disease /disorder model; drug screening /evaluation; fluorescent in situ hybridization; genetically modified animals; ibuprofen; immunocytochemistry; laboratory mouse; nervous system disorder chemotherapy; neural degeneration; neurogenetics; neuropharmacology; nonhuman therapy evaluation; nonsteroidal antiinflammatory agent; nuclear receptors; oxidative stress; simvastatin; therapy design /development

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.

描述（由申请人提供）：阿尔茨海默氏病（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，对阿尔茨海默氏病（AD）的遗传学，生物化学和病理学的理解已经提高，但神经退行性的生物学仍然是一个谜。已经开发了几种AD鼠标模型。这些近乎完美的“种族灭绝”重现了阿尔茨海默氏病的某些病理特征，但它们是不完美的“该表蛋白”。除其他外，它们无法再现神经元细胞死亡的表型。我们的实验室和其他实验室表明，人类AD大脑中处于危险中的神经元为重新进入细胞周期的证据提供了证据。我们已经提出，这种有丝分裂的尝试对神经元而言是致命的，是人类疾病中观察到的神经变性的近端原因。对表现出细胞周期事件（CCE）证据的神经元数量的定量分析预测了缓慢的死亡，需要数月的时间。我们现在有初步证据表明，尽管没有神经细胞死亡，但小鼠模型确实在适当的种群中启动了神经元细胞周期。疾病通过各个大脑区域的进展模仿了人类状况，并且在NSAID治疗的适当定时的3个月病程中可以阻止CCE的出现。在此修订后的应用中，我们建议在4种不同的AD小鼠模型中填写CCE的自然历史，并将其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。作为此目标的一部分，我们将对缺氧和免疫挑战进行测试，以驱动骑自行车神经元死亡的“第二次命中”。其次，我们将测试CCE对当前正在探索的NSAIDS疗法的反应，这些疗法目前正在用于治疗阿尔茨海默氏病：Ibuprofen，辛伐他汀和一种新方法GW3965，LXR受体的激动剂GW3965。我们将使用不同的APR转基因以及遗传背景作为变量之前和之后开始治疗。 CCE作为临床前AD试验中使用的新结果指标的潜在价值是5倍：它们易于检测；它们是神经元表型。他们与神经元细胞死亡有概念上的联系；它们都在老鼠和人物中发现。它们出现在疾病课程的早期。