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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：
10515406
负责人：
Peggi M Angel
金额：
--
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

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.

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