Neurogenesis in demented and non-demented individuals with Alzheimer's disease

描述(申请人提供)：阿尔茨海默病(AD)是最常见和最严重的与年龄相关的神经退行性痴呆。由于人口老龄化，预计每年将有1500万人受到阿尔茨海默病的影响。2050年，直接医疗保健费用远远超过1万亿美元。目前尚无治愈阿尔茨海默病的方法，迫切需要开发创新、有效的治疗靶点。值得注意的是，尽管存在通常与完全症状期AD相关的神经病理特征，但很少有人能保持认知完好无损。这些罕见病例的存在，在这里被称为非痴呆性阿尔茨海默病神经病理学(NDAN)，表明人类大脑有一种自然的方式来抵抗(或显著延迟)通常导致的神经毒性事件 阿尔茨海默病的认知障碍。因此，了解这种特殊耐药的细胞机制将揭示一个非常有效的治疗靶点。越来越多的证据和我们自己的初步数据表明，海马体(大脑中对学习和记忆起关键作用且受AD影响最大的区域)中的神经前体细胞数量在AD患者的大脑中显著减少，而在NDAN患者的大脑中增加。在这项提议中，我们将检验这样一种假设，即海马区新神经元的生成和整合是新近认识到的人脑抵抗AD相关认知衰退发展的内在能力的关键保护特征。在特定的目标1中，我们将测试这一假设，即正常生成和整合祖细胞衍生的新神经元伴随着NDAN个体完整的认知功能。在特定的目标2中，我们将检验海马神经前体细胞增殖和分化的表观遗传调控在AD患者和NAND患者之间存在差异的假设。这些研究将在提供给我们的尸检脑组织上进行，这是与俄勒冈州波特兰市俄勒冈健康科学大学莱顿AD中心病理学核心主任Randy Woltjer博士持续合作的一部分。在拟议的工作完成后，我们将描述与AD患者相比，NDAN受试者的神经发生过程，总体目标是证明尽管存在AD神经病理，但完整的/增加的神经发生与保留的认知能力之间存在显著关系。此外，我们将能够根据神经发生过程中涉及的特定路径，对观察到的NDAN个体认知阻力的潜在机制产生特定的工作假说。这是实现我们了解NDAN个体认知抵抗分子机制的第一个基本步骤，最终将使我们能够确定预防和/或治疗AD认知衰退的有效靶点。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common and severe age-associated neurodegenerative dementia. Because of an aging population, it is estimated that 15 million individuals will be affected by AD by the year. 2050, with a direct healt care cost far exceeding $1 trillion. There is currently no cure for AD, and the need to develop innovative, effective treatment targets is urgent. Notably, rare individuals remain cognitively intact despite the presence of neuropathological features usually associated with a fully symptomatic stage of AD. The existence of these unusual cases, herein referred to as Non-Demented with Alzheimer's disease Neuropathology (NDAN), suggests that there is a natural way for the human brain to resist (or significantly delay) the neurotoxic events that normally lead to cognitive impairment in AD. It follows that understanding the cellular mechanisms involved in such extraordinary resistance would reveal a very effective therapeutic target. A growing body of evidence and our own preliminary data show that the number of neural progenitor cells in the hippocampus (an area of the brain that plays a critical role in learning and memory and is most affected by AD) is significantly reduced in the brains of AD patients, while it is increased in brains of NDAN individuals. In this proposal, we will test the hypothesis that the generation and integration of new neurons in the hippocampus is a key protective feature of the newly appreciated intrinsic ability of the human brain to resist the development of AD-associated cognitive decline. In Specific Aim 1 we will test the sub-hypothesis that normal generation and integration of progenitor cell-derived new neurons accompany intact cognitive function in NDAN individuals. In Specific Aim 2 we will test the sub-hypothesis that the epigenetic regulation of proliferation and differentiation of hippocampal neural progenitor cells differ between AD patients and NAND individuals. These studies will be performed on autopsied brain tissue provided to us as part of an ongoing collaboration with Dr. Randy Woltjer, Director of the pathology core of the Layton AD Center at Oregon Health Science University, Portland, OR. At the completion of the work proposed, we will have characterized the process of neurogenesis in NDAN subjects as compared to AD individuals, with the overall objective of demonstrating the existence of a significant relationship between intact/increased neurogenesis and preserved cognitive competency despite the presence of AD neuropathology. Furthermore, we will be able to generate a specific working hypothesis on the mechanisms underlying the observed cognitive resistance of NDAN individuals based on specific pathways involved in the process of neurogenesis. This is the first fundamental step toward achieving our goal of understanding the molecular mechanisms of cognitive resistance in NDAN individuals, which will ultimately allow us to identify an effective target for prevention and/or treatment of cognitive decline in AD.