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

靶向驱动蛋白 5 活性治疗阿尔茨海默病

• 批准号: 10402218
• 负责人: Esteban M Lucero
• 金额: $ 1.5万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-06 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402218
• 关键词: ATP phosphohydrolase; Acute; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Amyloid; Animals; Architecture; Award; BRAIN initiative; Behavioral; Biochemical; Biological Assay; Biological Models; Brain; Caregivers; Cell Culture Techniques; Cell physiology; Cognitive; Defect; Dendritic Spines; Deposition; Depressed mood; Development; Disease; Disease Progression; Doctor of Philosophy; Elderly; Functional disorder; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Goals; Grant; Haplotypes; Health; Healthcare Systems; Hippocampus (Brain); In Vitro; Individual; Investigation; Kinesin; Knowledge; Leadership; Learning; Link; Long-Term Potentiation; Longevity; Measurement; Mediating; Memory; Memory impairment; Mentors; Mentorship; Microtubule Polymerization; Microtubules; Morphology; Motor; Mus; Neurites; Neurodegenerative Disorders; Neurons; Neurosciences; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Plant Roots; Population; Postdoctoral Fellow; Prevention; Process; Proteins; Public Health; Research; Research Personnel; Research Project Grants; Role; Route; Slice; Symptoms; Testing; Therapeutic Intervention; United States National Institutes of Health; Vertebral column; Wild Type Mouse; Work; Writing; abeta oligomer; aged; base; career; clinically significant; conditioned fear; density; disease phenotype; effective therapy; experimental study; healthspan; improved; innovation; interest; mouse model; nervous system disorder; novel; novel therapeutic intervention; overexpression; prevent; relating to nervous system; skills; small molecule; therapeutic target

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.

项目概要/摘要 阿尔茨海默病 (AD) 目前影响着超过 500 万美国人，是人类的重大负担 患者、护理人员和我们的医疗保健系统。目前，尚无已知的 AD 治疗方法，且已获批准 治疗不能逆转潜在的发病机制或抑制疾病进展。淀粉样蛋白沉积物和 它们相关的β淀粉样蛋白寡聚体（Aβ）与AD大脑中的多种细胞功能障碍有关 患者以及 AD 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、树突棘密度丧失和海马长时程增强（LTP）降低。许多 已经提出假设来解释 Aβ 促成这些表型的途径。 然而，尚未达成统一的机制理解。该项目建立在之前的基础上 研究表明 Aβ 抑制一组选定的微管运动蛋白的活性。他们之中， Kinesin-5/EG5/KIF11 由于其多种功能而受到特别关注，其中包括调节微管 稳定性、微管聚合和树突结构，所有这些都会受到 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 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) 过度表达 Kinesin-5 以维持其活性，或 2) 通过使用我们在 筛选阻断 Aβ 介导的 Kinesin-5 活性抑制。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测试，旨在 1) 确定 Kinesin-5 过度表达是否可以改善无 AD 病理的野生型小鼠的学习和记忆能力 以及在 AD 小鼠模型中，Kinesin-5 过表达是否可以挽救 Aβ 诱导的 AD 表型； 2） 确定 Kinesin-5 过度表达是否会改善长时程增强 (LTP) 以及 由 Aβ 引起的 LTP 可通过 Kinesin-5 过表达来挽救； 3) 确定Kinesin-5是否 过度表达影响野生型和 5xFAD 中的神经过程生长、脊柱密度和形态 老鼠。我们提出的研究还将加深对 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鉴定 与异常细胞功能相关的潜在机制可能会揭示一种全新的治疗方法 AD 的方法。该项目的创新之处在于将 Kinesin-5 确定为 AD 治疗的潜在治疗靶点包括：1) 探究尚未表征的 Kinesin-5 在学习、记忆和 AD 相关表型中的功能； 2）追求全新的 使用 Kinesin-5 活性作为治疗靶点来研究迫切需要的 AD 治疗方法。