Understanding the role of genetic admixture on Alzheimer’s Disease risk in Latíno Populations

项目总结/摘要 阿尔茨海默氏病（AD）目前影响超过500万美国人，并且是阿尔茨海默氏病患者的重大负担。 患者、护理人员和我们的医疗系统。目前，还没有已知的治疗AD的方法， 治疗不能逆转潜在的发病机制或抑制疾病进展。淀粉样沉积物和 其相关的β淀粉样蛋白低聚物（Aβ）与AD患者脑中的多种细胞功能障碍有关 在AD患者和AD的动物和细胞培养模型中。其中一些功能障碍包括微管 不稳定性，树突棘密度的损失，以及海马长时程增强（LTP）的抑制。许多 已经提出假说来解释Aβ促成这些表型的途径。 然而，至今还没有一个统一的机械理解。该项目建立在以前的 研究表明，Aβ抑制一组选定的微管马达蛋白的活性。其中， Kinesin-5/EG 5/KIF 11由于其多种功能而特别令人感兴趣，这些功能包括调节微管 稳定性、微管聚合和树突状结构，所有这些都受到Aβ的负面影响。 基于这些发现，本项目的长期目标是确定驱动蛋白-5活性是否可能 作为预防或逆转A β诱导的AD表型的有效靶点：1）通过 过表达驱动蛋白-5以维持其活性，或2）通过使用我们在一项研究中鉴定的小分子药物， 筛选阻断Aβ介导的驱动蛋白-5活性抑制的药物。为了实现这些目标，我们 使用小鼠模型系统结合细胞培养和生化试验，目的是：1）确定 驱动蛋白-5过表达是否改善无AD病理的野生型小鼠的学习和记忆 以及驱动蛋白-5过表达是否挽救了AD小鼠模型中Aβ诱导的AD表型; 2） 确定驱动蛋白-5过表达是否改善长时程增强（LTP）以及是否缺乏 由Aβ引起的LTP被驱动蛋白-5过表达拯救;和3）确定驱动蛋白-5是否 过表达影响野生型和5xFAD中的神经突起生长、棘密度和形态 小鼠我们提出的研究也将提供更多的了解驱动蛋白-5活性的作用， 调节不同的神经过程。这项工作的临床意义来自于鉴定 与异常细胞功能相关的潜在机制，可能揭示一种全新的治疗方法， 接近AD。该项目的创新之处在于将驱动蛋白-5鉴定为一种 治疗AD的潜在治疗靶点，包括：1）询问尚未表征的 Kinesin-5在学习、记忆和AD相关表型中的功能; 2）寻求一种全新的 研究迫切需要的AD治疗的途径，使用驱动蛋白-5活性作为治疗靶点。

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) currently affects more than 5 million Americans and is a significant burden for patients, caregivers, and our healthcare system. Currently, there is no known cure for AD, and approved therapies do not reverse the underlying pathogenesis or inhibit disease progression. Amyloid deposits and their associated amyloid beta oligomers (Aβ) are linked to multiple cellular dysfunctions in the brains of AD patients and in animal and cell culture models of AD. Some of these dysfunctions include microtubule instability, loss of dendritic spine density, and depressed hippocampal long-term potentiation (LTP). Many hypotheses have been put forward to explain the routes by which Aβ contributes to these phenotypes. However, a unified mechanistic understanding has not yet been achieved. This project builds on previous studies that have shown that Aβ inhibits the activity of a select set of microtubule motor proteins. Among them, Kinesin-5/EG5/KIF11 is of particular interest due to its diverse functions, which include regulating microtubule stability, microtubule polymerization, and dendritic architecture, all of which are negatively impacted by Aβ. Based on these findings, the long-term goal of this project is to determine whether Kinesin-5 activity may serve as an effective target for preventing or reversing A β -induced AD phenotypes: 1) by overexpressing Kinesin-5 to maintain its activity, or 2) by using small molecule drugs we identified in a screen that block Aβ-mediated inhibition of Kinesin-5 activity. In order to address these goals we are using a mouse model system in combination with cell culture and biochemical tests that aim to 1) Determine whether Kinesin-5 overexpression improves learning and memory in a wild-type mouse without AD pathology and whether Kinesin-5 overexpression rescues Aβ-induced AD phenotypes in the an AD mouse model; 2) Determine whether Kinesin-5 overexpression improves long-term potentiation (LTP) and whether deficits in LTP caused by Aβ are rescued by Kinesin-5 overexpression; and 3) Determine whether Kinesin-5 overexpression impacts neural process outgrowth, spine density, and morphology in wild-type and 5xFAD mice. Our proposed research will also provide an increased understanding of the role of Kinesin-5 activity in regulating diverse neuronal processes. The clinical significance of this work comes from the identification of underlying mechanisms linked to aberrant cellular functions that may uncover an entirely new therapeutic approach to AD. The innovative aspects of this project are rooted in the identification of Kinesin-5 as a potential therapeutic target for the treatment of AD and include: 1) interrogating of as yet uncharacterized functions of Kinesin-5 in learning, memory, and AD-related phenotypes; and 2) pursuing an entirely new avenue of investigation into desperately needed AD treatments using Kinesin-5 activity as a therapeutic target.