Targeting Kinesin-5 Activity for treatment of Alzheimer's disease

项目摘要/摘要 阿尔茨海默病(AD)目前影响着500多万美国人，对 病人、护理者和我们的医疗保健系统。目前，尚无治疗AD的已知方法，并已获批准 治疗方法不能逆转潜在的发病机制，也不能抑制疾病的发展。淀粉样蛋白沉积和 其相关的淀粉样β寡聚体(Aβ)与AD大脑中的多种细胞功能障碍有关 在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，树突棘密度丧失，以及海马长时程增强(LTP)受抑。许多 已经提出假说来解释Aβ对这些表型的贡献途径。 然而，目前还没有达成统一的机械性理解。这个项目建立在以前的基础上 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/EG5/KIF11因其多种功能而备受关注，其中包括调节微管 稳定性、微管聚合和树枝状结构，所有这些都受到Aβ的负面影响。 基于这些发现，该项目的长期目标是确定Kinesin-5的活性是否可以 作为预防或逆转β诱导的AD表型的有效靶点：1)通过 过度表达Kinesin-5以保持其活性，或2)通过使用我们在 筛选阻断Aβ介导的对Kinesin-5活性抑制的药物。为了实现这些目标，我们正在 使用小鼠模型系统，结合细胞培养和生化测试，目的是1)确定 Kinesin-5过表达是否改善了无AD病理的野生型小鼠的学习和记忆 以及Kinesin-5过表达是否挽救Aβ诱导的AD小鼠模型中的AD表型；2) 确定过表达Kinesin-5是否改善了长时程增强(LTP)，以及是否在 β引起的长时程增强可通过Kinesin-5的过度表达来挽救；以及3)决定Kinesin-5是否 在野生型和5xFAD中，过表达影响神经突起生长、脊柱密度和形态 老鼠。我们建议的研究还将提供对Kinesin-5活性在 调节不同的神经元过程。这项工作的临床意义来自于对 与细胞功能异常有关的潜在机制可能揭示一种全新的治疗方法 接近AD。该项目的创新方面植根于将Kinesin-5确定为一种 治疗阿尔茨海默病的潜在治疗靶点包括：1)讯问尚未定性的 Kinesin-5在学习、记忆和AD相关表型中的作用；以及2)追求一种全新的 使用激动素-5活性作为治疗靶点的迫切需要的AD治疗的研究途径。

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.