Relationship between Amyloid beta and Bioenergetics

β淀粉样蛋白与生物能学的关系

• 批准号: 10359050
• 负责人: Heather M. Wilkins
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359050
• 关键词: Abeta synthesis; Acids; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Area; Award; Biochemistry; Bioenergetics; Biology; Biometry; C-terminal; CRISPR/Cas technology; Career Choice; Cell Survival; Cell membrane; Data; Deoxyglucose; Development; Elderly; Electron Transport; Endosomes; Energy Metabolism; Environment; Enzymes; Event; Fibroblasts; Generations; Glucose; Glycolysis Inhibition; Goals; Grant; Human; Impairment; Individual; Induced pluripotent stem cell derived neurons; Intervention; Kansas; Length; Measures; Mediating; Medical center; Membrane Microdomains; Membrane Potentials; Mentors; Mitochondria; Modeling; Mutate; Neurology; Neurons; Oligomycins; Pathway interactions; Phosphorylation; Post-Translational Protein Processing; Production; Reactive Oxygen Species; Research; Role; SOD2 gene; System; Techniques; Testing; Training; Universities; Work; aging brain; amyloid precursor protein processing; base; beta secretase; beta-site APP cleaving enzyme 1; career; catalase; cholinergic; deprivation; design; experience; gamma secretase; glycosylation; induced pluripotent stem cell; insight; knock-down; mitochondrial membrane; new therapeutic target; novel; overexpression; palmitoylation; presenilin; presenilin-1; presenilin-2; respiratory; secretase; skills; trafficking; trans-Golgi Network

Project Summary/Abstract A clear relationship between amyloid precursor protein (APP), amyloid beta (Aβ), and mitochondria exists. APP and Aβ influence mitochondrial function, while mitochondrial function and bioenergetic pathways influence APP processing. Several studies indicate reductions in mitochondrial respiratory flux decrease Aβ production. Conversely, parameters which increase mitochondrial respiratory flux increase Aβ production. The overall goal of this study is to determine how bioenergetics influence APP processing pathways. Our preliminary data support a role for mitochondrial membrane potential and reactive oxygen species (ROS) in modulating the production of Aβ. Based on these findings, we hypothesize mitochondrial membrane potential and mitochondrial derived ROS influence APP processing. We will elucidate the involvement of these bioenergetic intermediates in APP processing pathways and determine how these changes occur. We hypothesize bioenergetics influence APP processing pathways by modulating the cellular localization and trafficking of APP, β-, and γ-secretases. To this end our proposed studies will explore fundamental relationships between mitochondria, energy metabolism-related phenomena, and Aβ production. These studies could potentially advance our understanding of Alzheimer’s disease (AD)-associated cascades while also providing translational and relevant insight. Understanding the relationship between Aβ production and bioenergetics will provide additional clues to the nexus between brain aging and AD, and novel therapeutic targets. This K99/R00 award is designed to further Dr. Wilkins’ career path by complimenting her current training and developing expertise in new areas. These new areas include reprogramming induced pluripotent stem cells (iPSCs), β-, and γ-secretase biology. At the University of Kansas Medical Center (KUMC), Dr. Wilkins will work in the neurology department, where the director of the Alzheimer’s Disease Center (Dr. Russell Swerdlow) is her primary mentor. To facilitate training in new techniques Dr. Wilkins will be assisted by a group of co-mentors. The co-mentors for this award include: Dr. Kenneth Peterson (KUMC) who will provide expertise on Crispr/Cas9 systems and reprogramming iPSCs; Dr. Robert Vassar (Northwestern University) who will provide expertise on β-secretase biology and manipulations, and Dr. Michael Wolfe (Harvard) who will provide expertise on γ-secretase biology and manipulations. Collaborators will assist with measuring APP processing (Dr. Bruce Yankner, Harvard) and biostatistical analysis (Dr. Jon Mankhen, KUMC). Dr. Wilkins’ expert mentoring team and collaborators, strong training environment, and prior research experience are imperative for advancing her career goals.

项目概要/摘要 淀粉样蛋白前体蛋白 (APP)、β 淀粉样蛋白 (Aβ) 和线粒体之间存在明确的关系。 APP 和 Aβ 影响线粒体功能，而线粒体功能和生物能途径影响 APP 处理。多项研究表明线粒体呼吸通量的减少会减少 Aβ 的产生。 离线时，增加线粒体呼吸通量的参数会增加 Aβ 的产生。 本研究的目的是确定生物能量学如何影响 APP 处理途径。 支持线粒体膜电位和活性氧 (ROS) 在调节 基于这些发现，我们破坏了线粒体膜电位并 线粒体衍生的 ROS 影响 APP 加工，我们将阐明这些生物能量的参与。 APP 途径处理中的中间体并确定这些变化如何发生。 生物能量学通过调节细胞定位和运输来影响 APP 加工途径 为此，我们提出的研究将探索 APP、β-和 γ-分泌酶之间的基本关系。 这些研究可能会影响线粒体、能量代谢相关现象和 Aβ 的产生。 增进我们对阿尔茨海默病（AD）相关级联的理解，同时还提供转化 以及相关的见解。了解 Aβ 产生与生物能量学之间的关系将提供帮助。 关于大脑衰老和 AD 之间关系的更多线索以及新的治疗靶点。 该 K99/R00 奖项旨在通过补充 Wilkins 博士目前的培训来进一步推进她的职业道路 并发展新领域的专业知识，包括重编程诱导多能干细胞。 Wilkins 博士将在堪萨斯大学医学中心 (KUMC) 进行细胞 (iPSC)、β- 和 γ-分泌酶生物学研究。 在神经科工作，阿尔茨海默病中心主任（Russell 博士） Swerdlow）是她的主要导师，为了促进新技术培训，威尔金斯博士将得到一个小组的协助。 该奖项的共同导师包括：Kenneth Peterson 博士（KUMC），他将提供 Crispr/Cas9 系统和 iPSC 重编程方面的专业知识；Robert Vassar 博士（西北大学） 他将提供 β-分泌酶生物学和操作方面的专业知识，Michael Wolfe 博士（哈佛大学）将提供 提供 γ-分泌酶生物学和操作方面的专业知识 合作者将协助测量 APP。 处理（Bruce Yankner 博士，哈佛大学）和生物统计分析（Jon Mankhen 博士，KUMC 威尔金斯博士）。 专家指导团队和合作者、强大的培训环境以及先前的研究经验 对于推进她的职业目标至关重要。

项目成果

Interactions between amyloid, amyloid precursor protein, and mitochondria.

淀粉样蛋白、淀粉样蛋白前体蛋白和线粒体之间的相互作用。

• 发表时间: 2023-02-27
• 影响因子: 3.9
• 作者: Wilkins; Heather M
• 通讯作者: Heather M

Cell type and sex specific mitochondrial phenotypes in iPSC derived models of Alzheimer's disease.

iPSC 衍生的阿尔茨海默病模型中的细胞类型和性别特异性线粒体表型。

• 发表时间: 2023
• 作者: Flannagan, Kaitlin;Stopperan, Julia A;Hauger, Brittany M;Troutwine, Benjamin R;Lysaker, Colton R;Strope, Taylor A;Csikos Drummond, Vivien;Gilmore, Caleb A;Swerdlow, Natalie A;Draper, Julia M;Gouvion, Cynthia M;Vivian, Jay L;Haeri, Mohammad;Sw
• 通讯作者: Sw

Mitophagy and the Brain.

线粒体自噬和大脑。

• 发表时间: 2020-12-18
• 影响因子: 5.6
• 作者: Swerdlow, Natalie S;Wilkins, Heather M
• 通讯作者: Wilkins, Heather M

Editorial: Systemic implications of Alzheimer's disease.

社论：阿尔茨海默病的系统影响。

• 发表时间: 2023
• 作者: Cortes, Constanza J;Thyfault, John P;Wilkins, Heather M
• 通讯作者: Wilkins, Heather M

Effects of Microglial Cytokines on Alzheimer's Disease-Related Phenomena.

小胶质细胞因子对阿尔茨海默病相关现象的影响。

• 发表时间: 2019
• 作者: Ji, Yan;Wang, Xiaowan;Kalicki, Colin;Menta, Blaise W;Baumgardner, Megan;Koppel, Scott J;Weidling, Ian W;Perez;Wilkins, Heather M;Swerdlow, Russell H
• 通讯作者: Swerdlow, Russell H