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: 10266216
• 负责人: Heng Du
• 金额: $ 37.42万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266216
• 关键词: Mitochondrial; ATP; Synthase; Dysfunction; Synaptic

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

计划主任/首席研究员（最后，第一，中间）：杜，亨 项目摘要： 越来越多的证据表明，线粒体功能障碍在发病机理中起着核心作用 阿尔茨海默氏病（AD）。 ATP生产和钙中的合成线粒体能力受损 已经提出保留为基础，以富含Aβ丰富的环境中的早期突触损伤。但是，详细 这种Aβ训练的合成线粒体定义的分子机制仍然难以捉摸。具体 这项拟议的研究背后的假设是线粒体F1FO ATP合酶通过寡霉素功能障碍 敏感性会议蛋白（OSCP）像差是突触线粒体缺陷的潜在原因，领先 在与广告相关条件下的突触失败。该假设首先基于以下观察：首先 线粒体F1FO ATP合酶在ATP生成中起着至关重要的作用。和未偶联的F1FO ATP合酶 构成线粒体通透性过渡孔（MPTP）的分子基础，其开口 线粒体能够缓冲钙的能力。它的功能障碍已在衰老的大脑和AD中暗示。但是 机制尚不清楚。第二，在初步研究中，我们发现线粒体F1FO ATP合酶功能障碍是过表达的AD动物模型中突出的合成线粒体缺陷 APP/Aβ（5XFAD小鼠）；第三，我们在广告大脑和突触线粒体中对这种酶的进一步研究 5XFAD小鼠已经显示其OSCP亚基的选择性损失以及OSCP与Aβ的相互作用。 此外，这种OSCP改变破坏了线粒体F1FO ATP合酶的完整性和功能。 最后，OSCP表达的恢复可缓解Aβ诱导的神经元线粒体和突触 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特定的工具 OSCP过表达5XFAD小鼠，一种诱导肽可抑制OSCP/Aβ相互作用以及遗传OSCP 下调并采用生物化学，细胞和分子生物学的多学科方法， 电生理学和活细胞成像。我们的目标是首先建立OSCP畸变和 突触线粒体F1FO ATP合酶在与AD相关条件下放松管制，并确定其对其对 突触线粒体功能障碍（特定AIM1）和突触损伤/认知障碍的发展 （特定AIM2）在5xFAD小鼠中。此外，我们将解决Aβ介导的线粒体的机制 OSCP缺乏症（特定AIM3）。积极的发现将提供线粒体和 AD的突触缺陷，并阐明了用于治疗AD的新型治疗策略的发展 通过保护OSCP。此外，可以扩展结果以进一步我们对线粒体的理解 其他神经退行性疾病的功能障碍和突触衰竭，淀粉样蛋白β（Aβ）沉积， ATP缺乏症和/或MPT激活。 OMB No. 0925-0001/0002（Rev. 08/12批准通过8/3​​1/2015）页面延续格式页面