Mitochondrial ATP Synthase Dysfunction and Synaptic Stress in Alzheimer's Disease

阿尔茨海默病中的线粒体 ATP 合酶功能障碍和突触应激

• 批准号: 9160954
• 负责人: Heng Du
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9160954
• 关键词: Address; Adopted; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Biochemistry; Bioenergetics; Brain; Buffers; Calcium; Cellular biology; Defect; Dendritic Spines; Development; Docking; Down-Regulation; Electrophysiology (science); Enzymes; Free Radicals; Functional disorder; Generations; Genetic; Goals; Impaired cognition; Injury; Learning; Light; Link; Mediating; Memory; Messenger RNA; Mitochondria; Mitochondrial Proton-Translocating ATPases; Molecular; Molecular Biology; Mus; Neurodegenerative Disorders; Neurons; Outer Mitochondrial Membrane; Pathogenesis; Pattern; Peptides; Permeability; Play; Predisposition; Principal Investigator; Production; Protein Deficiency; Protein Import; Protein Subunits; Proteolysis; Role; Stress; Synapses; Synaptic Transmission; Techniques; Ubiquitin; abeta accumulation; abeta deposition; aging brain; base; density; interdisciplinary approach; live cell imaging; mitochondrial dysfunction; mitochondrial permeability transition pore; novel; novel strategies; novel therapeutics; oligomycin sensitivity-conferring protein; overexpression; programs; protein expression; restoration; synaptic failure; synaptic function; tool; treatment strategy

Program Director/Principal Investigator (Last, First, Middle): Du, Heng Project summary: Increasing evidence has suggested that mitochondrial dysfunction plays a central role in the pathogenesis of Alzheimer's disease (AD) . Compromised synaptic mitochondrial capabilities in ATP production and calcium retention have been proposed to be underlying the early synaptic injury in Aβ-rich milieus. However, the detailed molecular mechanisms of such Aβ-potentiated synaptic mitochondrial deficits still remain elusive. The specific hypothesis behind this proposed study is that mitochondrial F1Fo ATP synthase dysfunction via oligomycin sensitivity conferring protein (OSCP) aberrations is a potential cause of synaptic mitochondrial defects, leading to synaptic failure in AD-relevant conditions. This hypothesis is firmly built on the following observations: First, Mitochondrial F1Fo ATP synthase plays a vital role in ATP generation ; and uncoupled F1Fo ATP synthase constitutes the molecular basis of mitochondrial permeability transition pore (mPTP) , the opening of which lowers mitochondrial ability to buffer calcium .Its dysfunction has been implicated in aging brain and AD; but the mechanisms are not well understood; Second, in preliminary studies we have found that mitochondrial F1Fo ATP synthase dysfunction is a prominent synaptic mitochondrial defect in an AD animal model overexpressing APP/Aβ (5xFAD mice); Third, our further studies on this enzyme in AD brains and synaptic mitochondria from 5xFAD mice have shown the selective loss of its OSCP subunit and the interaction of OSCP with Aβ. Furthermore, such OSCP alterations disrupt the integrity and function of mitochondrial F1Fo ATP synthase. Lastly, the restoration of OSCP expression mitigates Aβ-induced neuronal mitochondrial and synaptic dysfunction. In the proposed studies, we will adopt multiple tools including our newly generated neuron-specific OSCP overexpressing 5xFAD mice, a decoy peptide to inhibit OSCP/Aβ interaction as well as genetic OSCP down-regulation and apply multidisciplinary approaches of biochemistry, cell and molecular biology, electrophysiology and live cell imaging. We aim to firmly establish the link between OSCP aberrations and synaptic mitochondrial F1Fo ATP synthase deregulation in AD-relevant condition and determine its impact on the development of synaptic mitochondrial dysfunction (Specific aim1) and synaptic injury/cognitive impairments (specific aim2) in 5xFAD mice. Furthermore, we will address the mechanisms of Aβ-mediated mitochondrial OSCP deficiency (specific aim3). The positive findings will provide a novel mechanism of mitochondrial and synaptic defects in AD and shed light on the development of novel therapeutic strategies for the treatment of AD by the protection of OSCP. In addition, the results can be extended to further our understanding of mitochondrial dysfunction and synaptic failure in other neurodegenerative diseases which have Amyloid beta (Aβ) deposition, ATP deficiency, and/or mPT activation. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page

项目负责人/主要研究者（末、首、中）：杜恒 项目概要： 越来越多的证据表明，线粒体功能障碍在糖尿病的发病机制中起着重要作用。 阿尔茨海默病（AD）。受损的突触线粒体ATP产生和钙的能力 在富含Aβ的微环境中，滞留被认为是早期突触损伤的基础。然而，详细 这种Aβ增强的突触线粒体缺陷的分子机制仍然不清楚。具体 这项研究背后的假设是，线粒体F1 Fo ATP合酶功能障碍通过寡霉素 敏感性赋予蛋白（OSCP）畸变是突触线粒体缺陷的潜在原因， 与AD相关疾病中的突触失效有关这一假设是建立在以下观察基础上的：首先， 线粒体F1 Fo ATP合成酶在ATP生成中起着至关重要的作用， 构成线粒体通透性转换孔（mPTP）的分子基础， 降低线粒体缓冲钙的能力。它的功能障碍与大脑老化和AD有关;但 第二，在初步研究中，我们发现线粒体F1 Fo ATP合酶功能障碍是AD动物模型中一种显著的突触线粒体缺陷， APP/Aβ（5xFAD小鼠）;第三，我们对AD脑和突触线粒体中这种酶的进一步研究， 5xFAD小鼠表现出OSCP亚基的选择性丢失以及OSCP与Aβ的相互作用。 此外，这种OSCP改变破坏线粒体F1 Fo ATP合酶的完整性和功能。 最后，OSCP表达的恢复减轻了Aβ诱导的神经元线粒体和突触损伤。 功能障碍在拟议的研究中，我们将采用多种工具，包括我们新生成的神经元特异性 OSCP过表达5xFAD小鼠，一种抑制OSCP/Aβ相互作用以及遗传OSCP的诱饵肽 下调并应用生物化学、细胞和分子生物学的多学科方法， 电生理学和活细胞成像。我们的目标是牢固地建立OSCP畸变之间的联系， AD相关条件下突触线粒体F1 Fo ATP合酶失调及其对AD的影响 突触线粒体功能障碍（特异性aim 1）和突触损伤/认知障碍的发生 （特异性aim 2）。此外，我们将讨论Aβ介导的线粒体 OSCP缺陷（特定目标3）。这些积极的发现将提供一种新的机制， AD中的突触缺陷，并阐明了治疗AD的新治疗策略的发展 OSCP的保护。此外，该结果可以扩展到进一步了解线粒体 在具有淀粉样蛋白β（Aβ）沉积的其他神经退行性疾病中的功能障碍和突触失效， ATP缺乏和/或mPT活化。 OMB编号0925-0001/0002（2012年8月批准至2015年8月31日修订版）页码续页格式页码