Understand and probing disrupted glucose metabolism in Alzheimer's disease

项目摘要 阿尔茨海默病(AD)的特点是早期和显著的糖代谢改变和 线粒体呼吸酶。AD患者和无症状载脂蛋白E4携带者的局部脑葡萄糖 摄取减少。然而，我们不知道为什么会发生这些变化，它们如何有助于 神经退行性变，或者它们是否可以作为治疗的靶点。为了深入了解AD蛋白质的变化 葡萄糖代谢，我们开发了创新的方法来测量细胞和小鼠的葡萄糖代谢。 AD的模型。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 前体蛋白和载脂蛋白E4抑制糖代谢和呼吸链的不同步骤， 导致能量衰竭和磷酸戊糖途径(PPP)功能受损。总的目标是 我们提出的研究是为了确定muAPP和apoE4如何改变神经元中的葡萄糖代谢。我们会 通过两个具体目标实现这一目标。(一)我们将使用实时成像和质谱分析来测量 代谢通量，并确定突变APP和载脂蛋白E4如何扰乱糖代谢和生物能量学在 培养的神经元。(2)我们将使用代谢成像来确定muAPP和apoE4如何聚合以破坏 小鼠糖代谢随年龄的变化。总体而言，这些研究将提供重要的见解，以了解mutAPP是如何 和apoE4融合，扰乱葡萄糖代谢和能量产生，ii)发展为临床可翻译 AD的代谢成像方法，以及III)形成了使神经元正常化的新治疗策略的基础 阿尔茨海默病的代谢。

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.