Imaging and Reversibility of Cellular and Network Metabolic Dysfunction in Alzheimer's Disease

阿尔茨海默病细胞和网络代谢功能障碍的成像和可逆性

• 批准号: 10536491
• 负责人: ADAM Q BAUER
• 金额: $ 224.48万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536491
• 关键词: Address; Affect; Aftercare; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Amyloid deposition; Antibodies; Astrocytes; Biochemical Pathway; Brain; Cells; Cerebrum; Clinical Research; Dementia; Deposition; Disease; Energy Metabolism; Flavin-Adenine Dinucleotide; Functional disorder; Future; Glucose; Glycolysis; Human; Image; Imaging Techniques; Impairment; Lead; Link; Measures; Metabolic; Metabolic dysfunction; Metabolism; Methods; Microglia; Microscopic; Microscopy; Mitochondria; Mus; NADH; Nerve Degeneration; Neurons; Neurosciences; Nicotinamide adenine dinucleotide; Optics; Oxygen; Pathogenesis; Pathology; Patients; Physiological Processes; Population; Process; Respiratory Chain; Senile Plaques; System; Techniques; Technology; Testing; Time; Tissues; Translating; Treatment outcome; abeta accumulation; amyloid imaging; awake; brain metabolism; calcium indicator; cell type; effective therapy; fluorescence lifetime imaging; hemodynamics; human data; in vivo; indexing; metabolic rate; mitochondrial metabolism; mouse model; neuroimaging; neuronal patterning; optical imaging; relating to nervous system; serial imaging; spatiotemporal; treatment optimization; two-photon

PROJECT SUMMARY In Alzheimer’s disease (AD), Aβ accumulation and plaque formation precedes dementia by decades, suggesting that other downstream pathophysiological processes are responsible for precipitating symptomatic disease. Prior studies in humans reveal that brain metabolism is impaired in early AD, including an initial regional energy deficit with a superimposed, marked metabolic shift away from whole-brain and regional glycolysis. However, it is not yet clear how amyloid-induced metabolic dysfunction manifests at the cellular level and affects different cell types, how cellular metabolic dysfunction relates to tissue energy deficit and disruption of functional brain organization, and if and when this might be reversible. These questions have been difficult to answer due to technical challenges in spatiotemporally assessing cell type-specific mitochondrial function and energy metabolism, along with plaque deposition, at the microscopic and mesoscopic levels in vivo. Our central hypothesis is that plaque deposition induces metabolic dysfunction localized to specific cell types and/or cellular components. We further hypothesize that specific cellular changes in metabolic dysfunction differentially affect metabolism at the tissue level and functional brain organization at the regional and global levels. To test these hypotheses, our team has developed several technologies in mice including two-photon fluorescence lifetime imaging microscopy (TP-FLIM), multi-parametric photoacoustic microscopy (PAM), and wide-field optical imaging (WFOI). We will use these methods to measure concentrations of nicotinamide adenine dinucleotide (NADH), flavin adenine dinucleotide (FAD), cerebral metabolic rate of oxygen (CMRO2), and neural and hemodynamic activity. In addition to indicating overall mitochondrial activity, the ratio of NADH to FAD (N/F ratio) provides an optically-accessible index of metabolic shifts towards or away from glycolysis in vivo, a key early aspect of AD-related metabolic dysfunction. Since brain amyloid clearance is now readily achievable in both mice and humans, our approach will further allow us to determine whether the metabolic dysfunctions discovered from the efforts above are reduced following amyloid clearance. In the project, we aim to (Aim 1) determine the in vivo relationship between amyloid plaque deposition and cellular N/F ratio in AD mice at the microscopic level using TP-FLIM; (Aim 2) determine how amyloid plaque deposition and cellular metabolic dysfunction affect regional and global measures of tissue metabolism and functional brain organization using PAM and WFOI; and (Aim 3) determine whether amyloid plaque clearance reverses the metabolic abnormalities identified in Aims 1 and 2. Understanding the spatiotemporal relationship between Aβ accumulation, metabolic dysfunction, and functional brain organization from the cellular to systems level will be critical to revealing the mechanisms by which amyloid deposition affects downstream processes, and ultimately lead to neurodegeneration and symptomatic AD. Moreover, our study will reveal whether the metabolic dysfunction in AD is reversible or not.

项目总结 在阿尔茨海默病(AD)中，β积累和斑块形成早于痴呆症数十年，这表明 其他下游的病理生理过程是导致症状性疾病的原因。之前 对人类的研究表明，阿尔茨海默病早期大脑新陈代谢受损，包括最初的局部能量缺乏 叠加的，明显的代谢转移，远离全脑和局部糖酵解。然而，它并不是 但目前尚不清楚淀粉样蛋白诱导的代谢功能障碍如何在细胞水平表现并影响不同的细胞 细胞代谢功能障碍与组织能量缺乏和功能脑功能障碍的关系 组织，以及是否以及何时这可能是可逆的。这些问题一直很难回答，因为 时空评估特定细胞类型线粒体功能和能量的技术挑战 体内微观和介观水平的代谢以及斑块沉积。我们的中央 假设斑块沉积导致特定细胞类型和/或细胞的代谢功能障碍 组件。我们进一步假设，代谢功能障碍中的特定细胞变化对 组织层面的新陈代谢和区域和全球层面的脑功能组织。为了测试这些 假设，我们的团队已经在小鼠身上开发了几种技术，包括双光子荧光寿命 成像显微镜(TP-Flim)、多参数光声显微镜(PAM)和广域光学 成像(WFOI)。我们将使用这些方法来测量烟酰胺腺嘌呤二核苷酸的浓度 (NADH)、黄素腺嘌呤二核苷酸(FAD)、脑氧代谢率(CMRO2)、神经和 血流动力学活动。NADH与FAD的比值(N/F)除了指示线粒体的整体活性外，还包括 提供了体内糖酵解代谢转向或远离糖酵解的光学可及指数，这是早期的关键 AD相关代谢功能障碍的一个方面。由于大脑淀粉样蛋白清除现在很容易在两个 老鼠和人类，我们的方法将进一步允许我们确定是否发现了代谢功能障碍 上述努力在淀粉样蛋白清除后减少。在该项目中，我们的目标是(目标1)确定 阿尔茨海默病小鼠体内淀粉样斑块沉积与细胞N/F比值的微观关系 使用TP-Flim；(目标2)确定淀粉样斑块沉积和细胞代谢功能障碍如何影响 使用PAM和WFOI对组织新陈代谢和脑功能组织的区域性和全球性测量；以及 (目标3)确定淀粉样斑块清除是否能逆转AIMS 1中发现的代谢异常 以及2.了解β积聚、代谢功能障碍和 从细胞到系统水平的脑功能组织将是揭示这一机制的关键 哪些淀粉样蛋白沉积影响下游过程，并最终导致神经变性和 症状性AD。此外，我们的研究还将揭示AD的代谢功能障碍是否可逆。