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

描述（由申请人提供）：阿尔茨海默病（AD）是最常见和最严重的年龄相关性神经退行性痴呆。由于人口老龄化，估计到今年将有1500万人受到AD的影响。到2050年，直接医疗费用将远远超过1万亿美元。目前还没有治愈AD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AD的完全症状阶段相关的神经病理学特征，但很少有个体保持认知完整。这些不寻常的情况下，本文称为非痴呆与阿尔茨海默氏病神经病理学（NDAN）的存在，表明有一种自然的方式为人类大脑抵抗（或显着延迟）的神经毒性事件，通常导致 AD患者的认知障碍因此，了解这种异常抗性所涉及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（大脑中在学习和记忆中起关键作用的区域，受AD影响最大）中神经祖细胞的数量在AD患者的大脑中显着减少，而在NDAN个体的大脑中则增加。 在这个提议中，我们将测试的假设，即新的神经元的产生和整合在海马是一个关键的保护功能的新认识的内在能力的人类大脑抵抗AD相关的认知能力下降的发展。 在具体目标1中，我们将测试子假设，即在NDAN个体中，祖细胞衍生的新神经元的正常产生和整合伴随着完整的认知功能。在具体目标2中，我们将测试子假设，即海马神经祖细胞增殖和分化的表观遗传调控在AD患者和NAND个体之间不同。这些研究将对提供给我们的尸检脑组织进行，作为与波特兰俄勒冈州健康科学大学莱顿AD中心病理学核心主任Randy Woltjer博士持续合作的一部分。 在完成所提出的工作时，我们将表征NDAN受试者与AD个体相比的神经发生过程，总体目标是证明尽管存在AD神经病理学，但完整/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，我们将能够根据参与神经发生过程的特定途径，对观察到的NDAN个体认知抵抗的机制产生特定的工作假设。 这是实现我们理解NDAN个体认知抵抗分子机制的目标的第一个基本步骤，这将最终使我们能够确定预防和/或治疗AD认知下降的有效靶点。

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.