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

基本信息

批准号：
10704673
负责人：
Peggi M Angel
金额：
$ 76.07万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704673
关键词：
3-Dimensional Age Algorithms Alzheimer associated neurodegeneration Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Anabolism Architecture Astrocytes Biological Brain Brain region Carbohydrates Cell physiology Cells Central Nervous System 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 Human Image Impaired cognition Knowledge Link Longevity Maps Measures Memory Metabolic Metabolism Metadata Methodology Microglia Molecular Multiplexed Ion Beam Imaging Multivariate Analysis Neighborhoods Neurobiology Neurodegenerative Disorders Neuroglia Neurons Oral Pathogenesis Pathogenicity Pathology Pathway interactions Patients Physiology Play Polysaccharides Prefrontal Cortex Process Proteins Proteomics Regional Anatomy Research Personnel Role Sampling Slice Specimen Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Staging Study models Therapeutic Time Tissue imaging Tissues analysis pipeline 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 neuropathology protein folding sex single cell technology

项目摘要

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.

抽象的：阿尔茨海默氏病（AD）是一个毁灭性的诊断，并且有迫切需要了解基本的 AD的分子发病机理设计有效疗法。除了众所周知的AD病理学外，扰动的葡萄糖代谢也是AD的临床特征。糖原和N连接的聚糖是两个至关重要的重要但知识的葡萄糖代谢方面。糖原和N连接的聚糖都是复杂的碳水化合物在脑生理中起着至关重要的作用，例如认知，记忆形成和生命跨度。尽管这些途径在正常的大脑功能中很重要，但是否复杂在AD疾病进展过程中受到干扰仍然是神经生物学的关键知识差距。令人兴奋初步数据，我们发现了深层的糖原积累和蛋白质过度糖基化 AD和人类AD标本的小鼠模型的前额叶皮层。此外，我们发现了积极的在对97患者队列的分析中，糖原和Braak分期增加之间的相关性。最后，口头葡萄糖胺补充剂是UDP-N-乙酰葡萄糖胺生物合成的前体，N连接的基础聚糖进一步加剧了高糖基化，并导致5xfad小鼠的认知性能较差 AD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AD疾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决使用扰动复合碳水化代谢的细胞和细胞外来源最先进的单细胞技术。我们将通过多参数的协同整合来实现这一目标单细胞质谱成像方法。首先，我们将用临床定义复杂的碳水合物患者样本的病程和疾病进展（AIM 1）。然后，我们将询问细胞和细胞外正常和广告患者样品中的结构（AIM 2）。最后，我们将应用多模式集成进行跟踪 AD中复杂的碳水化合物扰动的细胞和细胞外起源（AIM 3）。这项研究将提供有关理想细胞，区域和临时特定治疗机会的关键新信息 AD的调节。总的来说，我们认为该提案的结果结果将是高度突出的阿尔茨海默氏病和其他神经退行性疾病的多个相关领域。