Deciphering the Glycan Code in Human Alzheimer’s Disease Brain

破译人类阿尔茨海默病大脑中的聚糖代码

• 批准号: 10515406
• 负责人: Peggi M Angel
• 金额: --
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515406
• 关键词: 3-Dimensional; Age; Algorithms; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Anabolism; Anatomy; Architecture; Astrocytes; Biological; Brain; Brain region; Carbohydrates; Cell physiology; Cells; Central Nervous System Diseases; Clinical; Clinical Course of Disease; Co-Translational Protein Processing; Code; Cognition; Complex; Data; Dementia; Development; Diagnosis; Dimensions; Disease; Disease Progression; Education; Endothelium; Event; Extracellular Matrix; Glucosamine; Glycogen; Goals; Heterogeneity; Hippocampus (Brain); Human; Image; Impaired cognition; Knowledge; Link; Longevity; Measures; Memory; Metabolic; Metabolism; Metadata; Methodology; Microglia; Molecular; Multiplexed Ion Beam Imaging; Multivariate Analysis; Neighborhoods; Neuraxis; Neurobiology; Neurodegenerative Disorders; Neuroglia; Neurons; Oral; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Physiology; Play; Polysaccharides; Prefrontal Cortex; Process; Proteins; Proteomics; Research Personnel; Role; Sampling; Slice; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staging; Study models; Therapeutic; Time; Tissue imaging; Tissues; analysis pipeline; base; carbohydrate metabolism; cellular imaging; cerebrovascular pathology; cognitive performance; cohort; design; effective therapy; extracellular; glucose metabolism; glycosylation; human disease; imaging approach; imaging platform; insight; mass spectrometric imaging; mouse model; multimodality; nanoscale; neuron loss; protein folding; sex; single cell technology

Abstract: Alzheimer’s disease (AD) is a devastating diagnosis and there is a critical need to understand the fundamental molecular pathogenesis of AD to design effective therapies. In addition to the well-known AD pathologies, perturbed glucose metabolism is also a clinical feature of AD. Glycogen and N-linked glycans are two critically important but understudied facets of glucose metabolism. Both glycogen and N-linked glycans are complex carbohydrates that play vital roles in brain physiology such as cognition, memory formation, and life span. Despite the importance of these pathways in normal brain function, whether complex carbohydrate metabolism are perturbed during AD disease progression remains a critical knowledge gap in neurobiology. In exciting preliminary data, we discovered profound glycogen accumulation and protein hyperglycosylation in the prefrontal cortex of both mouse models of AD and human AD specimens. Further, we found a positive correlation between increased glycogen and Braak staging in an analysis of a 97-patient cohort. Finally, oral glucosamine supplement, a precursor to UDP-N-acetylglucosamine biosynthesis, building block of N-linked glycans further exacerbated hyperglycosylation and led to poorer cognitive performance in the 5xFAD mouse model of AD. Based on these preliminary data, we hypothesize that aberrant complex carbohydrate metabolism are pathogenic processes during AD disease progression. The major objective of this study is to systematically resolve cellular and extracellular origins of perturbed complex carbohydrate metabolism using state-of-the-art single cell technologies. We will achieve this through synergistic integration of multi-parameter single-cell mass spectrometry imaging methodologies. First, we will define complex carbohydrates with clinical course and disease progression in patient samples (Aim 1). Then, we will interrogate cellular and extra-cellular architecture in normal and AD patient samples (Aim 2). Finally, we will apply multimodal integration to track cellular and extracellular origins of complex carbohydrate perturbation in AD (Aim 3). This study will provide critical new information regarding ideal cell-, region- and temporally-specific opportunities for therapeutic modulation of AD. Collectively, we believe the resultant findings from this proposal will be highly salient for multiple related fields of Alzheimer’s disease and other neurodegenerative disorders.

摘要： 阿尔茨海默病(AD)是一种毁灭性的诊断，迫切需要了解其根本原因 探讨AD的分子发病机制，设计有效的治疗方法。除了众所周知的AD病理之外， 糖代谢紊乱也是阿尔茨海默病的临床特征。糖原和N-连接的葡聚糖是两个至关重要的 葡萄糖代谢的重要但未被充分研究的方面。糖原和N-连接的多糖都是复杂的 碳水化合物在认知、记忆形成和寿命等大脑生理中发挥重要作用的碳水化合物。 尽管这些通路对正常的大脑功能很重要，但复杂的碳水化合物代谢 在AD疾病进展过程中受到干扰仍然是神经生物学中的一个关键知识缺口。在激动人心的 初步数据显示，我们发现在大鼠脑内糖原的大量积聚和蛋白质的高糖基化 两种AD模型小鼠和人类AD标本的前额叶皮质。此外，我们发现了一个积极的 97例患者队列分析中糖原升高与Braak分期的相关性。最后，口头发言 氨基葡萄糖补充剂，UDP-N-乙酰氨基葡萄糖生物合成的前体，N-连接的积木 多糖进一步加剧了5xFAD小鼠的高糖化并导致认知能力下降 AD的模型。基于这些初步数据，我们假设异常复杂的碳水化合物 代谢是阿尔茨海默病进展过程中的致病过程。这项研究的主要目的是 系统地解析扰动的复杂碳水化合物代谢的细胞和细胞外来源 最先进的单电池技术。我们将通过多参数的协同集成来实现这一点 单细胞质谱学成像方法。首先，我们将定义复杂的碳水化合物与临床 患者样本中的病程和疾病进展(目标1)。然后，我们将审问细胞内和细胞外 正常和AD患者样本中的结构(目标2)。最后，我们将应用多通道集成来跟踪 阿尔茨海默病复杂碳水化合物扰动的细胞和细胞外来源(目标3)。这项研究将提供 关于理想的细胞、区域和时间特定治疗机会的关键新信息 AD的调制。总体而言，我们相信，这项提案的结果将对 阿尔茨海默病和其他神经退行性疾病的多个相关领域。