Interactions between Mitochondria, ER, and Amyloid

项目摘要和摘要 阿尔茨海默病(AD)是通过tau的存在而诊断出的最常见的痴呆症 大脑中的缠结和淀粉样β蛋白(Aβ)斑块。β是由淀粉样前体蛋白(APP)产生的， 一种完整的膜蛋白。APP和Aβ定位于线粒体和线粒体相关膜 (妈妈)。MAMs是内质网(ER)-线粒体接触部位，与动脉粥样硬化 内质网和线粒体的功能。先前的研究表明，MAM的活动直接影响 将应用程序处理成β。我们假设APP在线粒体和MAM的定位决定了β 制作。 先前的研究表明，APP在线粒体、内质网和巨噬细胞膜上的定位会影响它们的功能，但 整体机制尚不清楚。AD患者存在线粒体和内质网功能障碍。受损的 线粒体生物能量学，增加氧化应激，并改变线粒体钙、胆固醇和 在AD模型中，磷脂代谢明显。已知MAMs调节这些功能 在AD中观察到线粒体和内质网之间的模式，以及MAM的上调。这一上调 MAM功能被认为是推动APP处理进入Aβ，并扰乱线粒体和内质网功能。 我们将在两个目标上检验我们的假设。我们将阐明APP本地化对Aβ的影响 制作并评估MAM功能是否会影响APP的本地化。我们将介绍APP和Aβ如何 生产与MAM功能相互作用。我们还将评估AD和细胞类型之间的特定变化 两性关系。解决MAM、APP和β生产之间的关系将提供新的见解 他们在AD病理中的作用。 这个F31奖项旨在通过赞扬泰勒·斯特罗普目前的训练来进一步推动她的职业道路 以及开发新领域的专业知识。这些新领域包括基因组编辑和诱导分化 多能干细胞(IPSCs)、线粒体/内质网生物学和APP生物学。在堪萨斯大学医学院 泰勒·斯特罗普将与她的导师阿尔茨海默氏症的威尔金斯博士和斯沃德洛博士合作 疾病研究中心。专家指导团队，强大的培训环境和研究经验 是推进泰勒·斯特罗普学术生涯目标的当务之急。

Project Summary and Abstract Alzheimer’s disease (AD) is the most common form of dementia diagnosed through the presence of tau tangles and amyloid beta (Aβ) plaques within the brain. Aβ is generated from amyloid precursor protein (APP), an integral membrane protein. APP and Aβ localize to mitochondria and mitochondrial associated membranes (MAMs). MAMs are endoplasmic reticulum (ER)-mitochondria contact sites and are associated with altered function of both the ER and mitochondria. Previous studies have shown that MAM activity directly influences APP processing into Aβ. We hypothesize that localization of APP at mitochondria and MAMs dictates Aβ production. Prior studies indicate APP localization at the mitochondria, ER, and MAMs affects their function, but an overall mechanism is not understood. Mitochondrial and ER dysfunction are observed in AD. Impaired mitochondrial bioenergetics, increased oxidative stress, and altered mitochondrial calcium, cholesterol, and phospholipid metabolism are evident in models of AD. MAMs are known to modulate these functional modalities between mitochondria and ER, and upregulation of MAMs is observed in AD. This upregulation of MAM function is hypothesized to drive APP processing into Aβ and disrupt mitochondrial and ER function. We will test our hypothesis in two aims. We will elucidate the effects of APP localization on Aβ production and evaluate if MAM function influences localization of APP. We will address how APP and Aβ production interact with MAM function. We will also evaluate AD and cell-type specific changes between these relationships. Addressing the relationship between MAMs, APP, and Aβ production will provide novel insights into their roles in AD pathology. This F31 award is designed to further Taylor Strope’s career path by complimenting her current training and developing expertise in new areas. These new areas include genome editing and differentiation of induced pluripotent stem cells (iPSCs), mitochondrial/ER biology, and APP biology. At the University of Kansas Medical Center (KUMC), Taylor Strope will work with her mentors, Drs. Wilkins and Swerdlow of the Alzheimer’s Disease Research Center. The expert mentoring team, strong training environment, and research experience are imperative for advancing Taylor Strope’s academic career goals.