Understand and probing disrupted glucose metabolism in Alzheimer's disease

了解并探索阿尔茨海默病中葡萄糖代谢紊乱

基本信息

批准号：
9802793
负责人：
Myriam Marianne Chaumeil
金额：
$ 359.73万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9802793
关键词：
Ablation Age Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Amyloid beta-Protein Precursor Anaerobic Bacteria Area Bioenergetics Biological Assay Biology Brain Carbon Cell Line Cell Respiration Cell model Consumption Diabetes Mellitus Dietary Intervention Disease Energy Metabolism Enzymes Exposure to Failure Fluorescence Resonance Energy Transfer Functional disorder Glucose Glucose Transporter Glycolysis Goals Hippocampus (Brain)Human Image Impairment Individual Investigation J20 mouse Knock-in Mass Spectrum Analysis Measures Memory impairment Metabolic Mitochondria Mouse Protein Mus Nerve Degeneration Neurons Oxidative Phosphorylation Oxygen Pathway interactions Patients Pattern Pentosephosphate Pathway Physiological Play Process Production Proteins Pyruvate Pyruvate Metabolism Pathway Resistance Respiration Respiratory Chain Role Slice Testing Therapeutic Uses Transgenic Mice Up-Regulation Wild Type Mouse abeta deposition aerobic glycolysis age related apolipoprotein E-4 blood glucose regulation clinically translatable early detection biomarkers extracellular glucose analog glucose metabolism glucose uptake imaging approach in vivo innovation insight magnetic resonance spectroscopic imaging metabolic imaging metabolic profile metabolomics mouse model mutant neuronal metabolism novel novel therapeutic intervention postnatal relating to nervous system respiratory enzyme sensor targeted treatment uptake

项目摘要

Project Summary Alzheimer's disease (AD) is characterized by early and prominent changes in glucose metabolism and mitochondrial respiratory enzymes. In AD patients and asymptomatic apoE4 carriers regional brain glucose uptake is decreased. However, we do not understand why these changes occur, how they contribute to neurodegeneration, or whether they can be targeted therapeutically. To gain insight into how AD proteins change glucose metabolism, we developed innovative assays to measure glucose metabolism in cellular and mouse models of AD. With this approach, we can test our central hypothesis that, in AD, mutant (mut)-amyloid precursor protein (mutAPP) and ApoE4 inhibit distinct steps in glucose metabolism and the respiratory chain, resulting in energy failure and impaired pentose phosphate pathway (PPP) function. The overall objective of our proposed study is to determine how mutAPP and apoE4 alter glucose metabolism in neurons. We will accomplish this objective in two specific aims. (1) We will use live imaging and mass spectrometry to measure metabolic fluxes, and determine how mutAPP and ApoE4 disrupt glucose metabolism and bioenergetics in cultured neurons. (2) We will use metabolic imaging to determine how mutAPP and apoE4 converge to disrupt glucose metabolism with age in mice. Overall, these studies will i) provide important insights into how mutAPP and apoE4 converge to disrupt glucose metabolism and energy production, ii) develop clinically translatable metabolic imaging approaches for AD, and iii) form the basis for new therapeutic strategies to normalize neuronal metabolism in AD.

项目概要阿尔茨海默病 (AD) 的特点是葡萄糖代谢的早期和显着变化以及线粒体呼吸酶。 AD 患者和无症状 apoE4 携带者区域脑葡萄糖吸收量减少。然而，我们不明白为什么会发生这些变化，它们如何促进神经退行性疾病，或者它们是否可以作为治疗目标。深入了解 AD 蛋白如何变化葡萄糖代谢，我们开发了创新的检测方法来测量细胞和小鼠的葡萄糖代谢 AD 模型。通过这种方法，我们可以检验我们的中心假设，即在 AD 中，突变 (mut)-淀粉样蛋白前体蛋白 (mutAPP) 和 ApoE4 抑制葡萄糖代谢和呼吸链中的不同步骤，导致能量衰竭和磷酸戊糖途径（PPP）功能受损。总体目标我们提出的研究是确定 mutAPP 和 apoE4 如何改变神经元中的葡萄糖代谢。我们将通过两个具体目标来实现这一目标。 (1) 我们将使用实时成像和质谱来测量代谢通量，并确定 mutAPP 和 ApoE4 如何破坏葡萄糖代谢和生物能学培养的神经元。 (2)我们将使用代谢成像来确定mutAPP和apoE4如何聚合以破坏小鼠的葡萄糖代谢随年龄的变化。总的来说，这些研究将 i) 为 mutAPP 如何和 apoE4 聚合以破坏葡萄糖代谢和能量产生，ii) 开发可临床转化的 AD 的代谢成像方法，以及 iii) 为神经元正常化的新治疗策略奠定了基础 AD 中的新陈代谢。