Investigating the role of BDNF in the Stem Cell-mediated Restoration of Cognition

描述（由申请人提供）：阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，影响500万65岁及以上的美国人，预计到2030年，这种患病率将增加50%以上。因此，AD对美国人的健康和福祉是一个严重且日益严重的挑战，必须致力于减轻其影响。干细胞移植是治疗阿尔茨海默病（AD）的一种新兴的潜在疗法，最近我们的实验室发现将神经干细胞（NSC）植入具有阿尔茨海默病（AD）病理特征的小鼠的海马中可以逆转这些动物的认知缺陷。值得注意的是，这些细胞似乎对AD的病理学特征没有影响，相反，似乎正在影响宿主细胞以补偿由病理学引起的损害。在这种基于干细胞的方法可以在AD患者中实施之前，重要的是要精确地了解这些对宿主细胞的影响是如何介导的。此外，对这种恢复机制的详细了解可能有助于改进该技术或指导新的药理学方法的开发。有令人信服的证据表明，脑源性神经营养因子（BDNF），一种对记忆相关突触重塑至关重要的蛋白质，是NSCs恢复AD病理小鼠认知机制的重要组成部分。目前的项目将探讨BDNF在神经干细胞介导的认知恢复中的作用。通过移植BDNF敲低或敲除的NSC降低海马BDNF水平来确定必要性。此外，该项目将研究NSC移植的长期疗效，以及是否可以通过工程化NSC表达AD病理减轻酶neprilysin来改善疗效。最近基于干细胞的治疗阿尔茨海默病的方法已被证明可以逆转动物模型中的记忆丧失。该项目将研究一种特定的生长因子，脑源性神经营养因子（BDNF）和阿尔茨海默病病理学减轻酶，脑啡肽酶在进行这种干细胞介导的逆转中的关键作用。更好地了解干细胞中的BDNF和脑啡肽酶将有助于改善基于干细胞的疗法或指导药物开发，以减少这种毁灭性疾病的影响。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects 5 million Americans age 65 and older, and this prevalance is expected to increase more than 50% by the year 2030. AD, therefore, is a serious and growing challenge to the health and well-being of Americans, and research must be devoted to lessening its impact. An emerging potential therapy for Alzheimer's Disease (AD) is the transplantation of stem cells, and recently our laboratory has found that implanting neural stem cells (NSC) into the hippocampus of mice with the hallmarl< pathological features of AD reverses these animals' cognitive deficits. Remarkably, these cells seem to have no effect on the pathological features of AD, and instead seem to be influencing host cells to compensate for the detriment caused by the pathology. Before this stem cell-based approach can be implemented in AD patients, it is important to understand precisely how these influences on host cells are mediated. In addition, a detailed understanding of this restorative mechanism may facilitate refinement of the technique or direct the development of novel pharmacological approaches. There is compelling evidence that brain-derived neurotrophic factor (BDNF), a protein that is critical for memory-associated synaptic remodeling, is an important component ofthe mechanism by which NSCs restore cognition in mice with AD pathology. The current project will investigate the role of BDNF in the NSC-mediated restoration of cognition. Necessity will be determined by decreasing hippocampal BDNF levels by transplanting NSCs that have BDNF knocked-down or knocked-out. In addition, this project will examine the long-term efficacy of NSC transplantation, and whether efficacy can be improved by engineering NSCs to express an AD pathology-reducing enzyme, neprilysin. Recent stem cell-based approaches to treating Alzheimer's disease have been shown to reverse memory loss in animal models.. This project will investigate the critical role of a specific growth factor, brain-derived neurotrophic factor (BDNF), and an Alzheimer's pathology-reducing enzyme, neprilysin, in carrying out this stem cell-mediated reversal. A better understanding of BDNF and neprilysin in stem cells will help to improve stem cell-based therapies or direct drug development that reduces the impact of this devastating disease.