Relationships between APP and Mitochondria

APP与线粒体的关系

• 批准号: 10658594
• 负责人: Heather M. Wilkins
• 金额: $ 73.92万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658594
• 关键词: Abeta synthesis; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Astrocytes; Autophagosome; Bioenergetics; Cells; Clinical Trials; DNA copy number; Data; Degradation Pathway; Drug Design; Electron Microscopy; Electron Transport; Engineering; Failure; Genes; Goals; Impairment; Knock-out; Knockout Mice; Knowledge; Label; Length; Literature; Measures; Membrane Potentials; Metabolic; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Modeling; Mouse Protein; Mus; Neurons; Nuclear; Oxygen Consumption; PINK1 gene; Pathogenesis; Pathway interactions; Pattern; Proteomics; Reactive Oxygen Species; Role; Sex Differences; Swelling; Testing; Transgenic Organisms; amyloid precursor protein processing; cell type; drug discovery; experimental study; fatty acid oxidation; in vitro Model; in vivo; in vivo Model; induced pluripotent stem cell; knock-down; mitochondrial dysfunction; mitochondrial membrane; new therapeutic target; overexpression; protein expression; sex; therapeutic target

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.

项目总结/摘要 我们将确定APP和APP蛋白水解产物对线粒体自噬的影响， 生物能量功能我们假设淀粉样前体蛋白（APP）通过以下途径促进线粒体自噬： 与PINK 1和p62的直接相互作用。我们进一步假设APP表达的缺失或减少 线粒体定位通过抑制线粒体自噬影响线粒体功能。 代谢缺陷在阿尔茨海默病（AD）中是突出的。淀粉样蛋白与 在文献中描述了前体蛋白（APP）和线粒体，但APP的功能在 线粒体还不太清楚。 APP和Aβ定位于线粒体并可改变线粒体功能。我们的数据显示 线粒体膜电位与Aβ产生和APP线粒体定位直接相关。 在线粒体自噬增加的条件下，APP线粒体定位增加。我们的数据显示 APP在线粒体或APP表达缺失，降低线粒体电子传递链（ETC）功能 和线粒体自噬总的来说，我们的数据支持APP在调节线粒体自噬和生物能量通量中的作用。一 我们目前的知识差距是，这些观察结果是否归因于全长APP或APP 加工产品。我们将在这里解决这个知识差距。 线粒体、生物能量学、线粒体自噬和APP之间的关系是明显的。我们的数据支持 APP在线粒体的定位、生物能量功能和线粒体自噬之间的关系。我们假设 线粒体APP的缺失改变了生物能流（Aim 1）和线粒体定位的APP 促进线粒体自噬（Aim 2）。本研究的总体目标是了解APP及其 在线粒体自噬和生物能量通量的衍生物。 我们将在两个目标中使用体内和体外模型。体外模型包括工程诱导的 具有野生型（WT）APP、APP敲除或线粒体定位的多能干细胞（iPSC）细胞 不合格APP（3 M APP）表达。工程化的iPSC将分化为神经元和星形胶质细胞。在 体内模型将包括非转基因、转基因WT APP小鼠和APP敲除小鼠。两者在体内的使用 和体外模型允许阐明细胞类型特异性效应（体外模型）和性别差异（在 体内）。 我们将测量在原生条件下和在以下条件下提出的模型中的端点： APP处理被抑制或增加。我们将确定全长APP与APP处理的作用 线粒体自噬和生物能通量途径中的产物。