Dissecting the Interplay between proteasome dysfunction, proteostasis and Alzheimer's disease

剖析蛋白酶体功能障碍、蛋白质稳态和阿尔茨海默病之间的相互作用

• 批准号: 10167581
• 负责人: Andrew Michael Pickering
• 金额: $ 63.94万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10167581
• 关键词: Dissecting; Interplay; between; proteasome; dysfunction

Project Summary/Abstract Alzheimer’s disease (AD) affects 5.5 million Americans producing cognitive deficits and mortality. There is no treatment for AD, thus, development of interventions to slow or reverse AD symptoms is a critical area of research. Furthermore, AD is difficult to detect until substantial neurodegeneration has already occurred. This proposal investigates proteasome function both as an intervention to AD symptoms and as a tool for early stage diagnosis in peripheral tissues. A key symptom of AD is proteostatic dysfunction. Patients as well as animal models of AD have a pronounced decline in proteasome function. Using in vivo invertebrate and in vitro vertebrate models of AD, we have found that genetic and pharmacologic augmentation of proteasome delays cognitive and neurodegenerative symptoms, while reducing proteasome function accelerates AD progression. This proposal builds on the above exciting findings and is designed in response to RFA-AG-18-020, Role of Peripheral Proteostasis on Brain Aging and Alzheimer's Disease. The proposal has three goals. The first goal is to develop a mechanistic understanding of how proteasome dysfunction is linked to AD progression. We present, and test, two hypotheses to explain this interplay. The first hypothesis is that the proteasome has a key role in prevention of AD progression through degradation of β-amyloid (Aβ) machinery and or its substrate (APP, BACE1, and γ-secretase activators, are all targets of proteasome degradation). If our results bear out, it would indicate that age-related declines in proteasome function result in a build-up of these proteins, which accelerates AD progression. The second hypothesis we test is if proteasome dysfunction triggered by Aβ inhibition drives downstream neurodegeneration rather than altering Aβ accumulation. Proteasome dysfunction on its own is shown to cause neurodegeneration and synaptic loss. If our findings are consistent with this, it would indicate that proteasome dysfunction caused by Aβ inhibition is an intermediator for AD-induced cognitive deficits and neurodegeneration. The second goal is to test if AD triggers proteasome dysfunction in peripheral tissues as a diagnostic tool for early AD screening. We have initial findings supporting this. The third goal is to test if genetic or pharmacologic proteasome augmentation is a germane target for treatment of AD-like symptoms in mice that model AD. These experiments are designed to advance us toward the long-term goal of developing novel screening tools and treatments for AD in humans. This multi-PI project, led by a new investigator, seeks to develop a mechanistic understanding of the interplay between the proteasome and AD, test the efficacy of genetic and pharmacologic proteasome manipulation as an AD intervention, and test the viability of peripheral proteasome dysfunction as an early diagnosis tool. Our innovative models, state-of-the-art methods, expert investigative team, compelling preliminary data, novel pharmacologics, new transgenic lines, and diverse biological systems increase the likelihood of successfully achieving our goals and provide potential for clinical relevance.

项目摘要/摘要 阿尔茨海默病(AD)影响着550万美国人，导致认知缺陷和死亡。那里 不能治疗阿尔茨海默病，因此，开发干预措施减缓或扭转AD症状是 研究。此外，在发生实质性的神经变性之前，阿尔茨海默病很难被发现。这 一项提案研究了蛋白酶体的功能，作为干预AD症状和早期诊断的工具 外周组织分期诊断。阿尔茨海默病的一个关键症状是蛋白抑制功能障碍。患者以及 阿尔茨海默病动物模型蛋白酶体功能明显下降。利用体内无脊椎动物和体外 在脊椎动物AD模型中，我们发现蛋白酶体的遗传和药物增强延迟 认知和神经退行性症状，同时降低蛋白酶体功能会加速AD的进展。 本提案建立在上述令人振奋的发现基础上，并根据RFA-AG-18-020进行设计， 外周蛋白平衡在脑老化和阿尔茨海默病中的作用。该提案有三个目标。 第一个目标是发展一种对蛋白酶体功能障碍如何与 广告进展。我们提出并检验了两个解释这种相互作用的假设。第一个假设是 蛋白酶体通过降解β-淀粉样蛋白(A-β)机制在阻止AD进展中发挥关键作用 和/或其底物(APP、BACE1和γ-分泌酶激活剂，都是蛋白酶体降解的靶标)。如果 我们的结果证实，这将表明与年龄相关的蛋白酶体功能下降导致 这些蛋白质加速了AD的进展。我们检验的第二个假设是蛋白酶体功能障碍 由Aβ抑制触发的基因会导致下游神经退行性变，而不是改变Aβ的积累。 蛋白酶体功能障碍本身被证明会导致神经变性和突触丧失。如果我们的发现是 与此一致的是，这表明Aβ抑制引起的蛋白酶体功能障碍是一个中介 治疗阿尔茨海默病引起的认知缺陷和神经退化。第二个目标是测试AD是否触发 外周组织蛋白酶体功能障碍作为早期AD筛查的诊断工具。我们有 初步调查结果支持这一点。第三个目标是测试基因或药物蛋白酶体 对于建立AD模型的小鼠，增强是治疗AD样症状的关键靶点。这些 实验旨在推动我们朝着开发新的筛查工具和 人类阿尔茨海默病的治疗。这个多PI项目，由一名新的调查员领导，试图开发一种机械式的 了解蛋白酶体与阿尔茨海默病之间的相互作用，测试遗传和药物的疗效 蛋白酶体操作作为AD的干预，并测试外周蛋白酶体功能障碍的生存能力 一种早期诊断工具。我们创新的模式，最先进的方法，专家调查团队，令人信服 初步数据、新的药理、新的转基因品系和多样化的生物系统增加了 成功实现我们的目标的可能性，并提供潜在的临床相关性。