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，人们对阿尔茨海默病 (AD) 的遗传学、生物化学和病理学的了解有所进展，但神经退行性变的生物学仍然是个谜。现已开发出多种 AD 小鼠模型。这些近乎完美的“基因拷贝”再现了阿尔茨海默病的一些病理特征，但它们是不完美的“表型拷贝”。除此之外，它们无法重现神经元细胞死亡的表型。我们的实验室和其他实验室已经证明，人类 AD 大脑中处于死亡风险的群体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于神经元来说是致命的，并且是在人类疾病中观察到的神经变性的最直接原因。对表现细胞周期事件（CCE）证据的神经元数量进行定量分析预测缓慢死亡，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群体中启动了神经元细胞周期。该疾病在各个大脑区域的进展模仿了人类的状况，而且重要的是，适时的 3 个月 NSAID 治疗疗程可以阻止 CCE 的出现。在这个修订后的申请中，我们建议完成对 4 种不同 AD 小鼠模型中 CCE 自然史的描述，​​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驱动循环神经元死亡的“第二次打击”的功效。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 NSAIDS 疗法的反应：布洛芬、辛伐他汀和一种新方法 GW3965（一种 LXR 受体激动剂）。我们将在 CCE 首次出现之前和之后启动治疗，使用不同的 APR 转基因以及遗传背景作为变量。 CCE 作为临床前 AD 试验中使用的新结果衡量标准的潜在价值有 5 倍：它们易于检测；它们是一种神经元表型；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发现；它们出现在病程早期。