Relationships between APP and Mitochondria

项目摘要/摘要 我们将确定APP和APP蛋白分解产物对有丝分裂和 生物能量功能。我们假设淀粉样前体蛋白(APP)通过 与PINK1和P62的直接相互作用。我们进一步假设APP表达的丧失或减少 线粒体定位通过抑制线粒体吞噬作用影响线粒体功能。 代谢缺陷在阿尔茨海默病(AD)中非常突出。淀粉样蛋白之间有明确的关系 前体蛋白(APP)和线粒体在文献中被描述，但APP的功能在 线粒体还没有被很好地理解。 APP和Aβ定位于线粒体，可以改变线粒体的功能。我们的数据显示 线粒体膜电位与Aβ的产生和APP的线粒体定位直接相关。 在线粒体吞噬增加的情况下，APP的定位增加。我们的数据显示 APP位于线粒体或APP表达缺失，降低线粒体电子传输链(ETC)功能 和有丝分裂症。总体而言，我们的数据支持APP在调节有丝分裂和生物能量通量方面的作用。一个 我们目前的知识差距是，这些观察结果是否归因于完整的应用程序或应用程序 加工产品。我们将在这里解决这一知识差距。 线粒体、生物能量学、有丝分裂和APP之间的关系是显而易见的。我们的数据支持 APP在线粒体的定位、生物能量功能与有丝分裂的关系。我们假设 线粒体APP的丢失改变了生物能通量(AIM 1)和线粒体定位的APP 促进有丝分裂(目标2)。本研究的总体目标是了解APP及其 有丝分裂和生物能通量中的衍生物。 我们将在两个目标上使用体内和体外模型。体外模型包括工程诱导 具有野生型(WT)APP、APP基因敲除或线粒体定位的多潜能干细胞(IPSC) APP(3M APP)表情不称职。经过工程改造的IPSCs将分化为神经元和星形胶质细胞。在……里面 活体模型将包括非转基因、转基因WT APP小鼠和APP基因敲除小鼠。两者在体内的应用 体外模型允许阐明细胞类型的特定效应(体外模型)和性别差异(在 Vivo)。 我们将测量在本地条件下和在以下条件下提出的模型中的端点 应用程序处理被禁止或增加。我们将确定完整应用程序与应用程序处理的角色 有丝分裂和生物能通量途径中的产物。

Project Summary/Abstract We will determine the effects of APP and APP proteolytic products on mitophagy and bioenergetic function. We hypothesize that amyloid precursor protein (APP) facilitates mitophagy through direct interactions with PINK1 and p62. We further hypothesize that loss of APP expression or reduced mitochondrial localization affects mitochondrial function through inhibition of mitophagy. Metabolic deficiencies are prominent in Alzheimer’s disease (AD). A clear relationship between amyloid precursor protein (APP) and mitochondria is described in the literature but the function of APP at mitochondria is not well understood. APP and Aβ localize to mitochondria and can alter mitochondrial function. Our data show that mitochondrial membrane potential directly correlates with Aβ production and APP mitochondrial localization. Under conditions of increased mitophagy APP mitochondrial localization is increased. Our data indicate loss of APP at mitochondria or loss of APP expression, reduces mitochondrial electron transport chain (ETC) function and mitophagy. Overall, our data support a role of APP in modulating mitophagy and bioenergetic flux. A current gap in our knowledge is if these observations are attributed to full-length APP or APP processing products. We will address this knowledge gap here. A relationship between mitochondria, bioenergetics, mitophagy, and APP is evident. Our data support a relationship between APP localization at mitochondria, bioenergetic function, and mitophagy. We hypothesize that loss of APP at mitochondria alters bioenergetic flux (Aim 1) and mitochondrial localized APP facilitates mitophagy (Aim 2). The overall goal of this study is to understand the role of APP and its derivatives in mitophagy and bioenergetic flux. We will use in vivo and in vitro models across two aims. In vitro models include engineered induced pluripotent stem cells (iPSC) cells with either wild-type (WT) APP, APP knockout, or mitochondrial localization incompetent APP (3M APP) expression. Engineered iPSCs will be differentiated to neurons and astrocytes. In vivo models will include non-transgenic, transgenic WT APP mice and APP knockout mice. Use of both in vivo and in vitro models allows for elucidation of cell type specific effects (in vitro models) and sex differences (in vivo). We will measure endpoints in the models proposed under native conditions and under conditions where APP processing is inhibited or increased. We will determine the role of full-length APP versus APP processing products in mitophagy and bioenergetic flux pathways.