MALDI imaging of glial scar-forming glycans in Alzheimers disease

阿尔茨海默病中胶质疤痕形成聚糖的 MALDI 成像

• 批准号: 10300280
• 负责人: Kimberly Michele Alonge
• 金额: $ 26.48万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300280
• 关键词: Affect; Aging; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Amyloid beta-Protein; Area; Astrocytes; Autopsy; Biological; Biological Process; Brain; Brain region; Buffers; Charge; Chondroitin Sulfate A; Chondroitin Sulfates; Cicatrix; Clinical; Code; Cognitive; Couples; Coupling; Data; Dermatan Sulfate; Deuterium; Development; Diffusion; Disaccharides; Disease; Extracellular Matrix; Failure; Frontal gyrus; Functional disorder; Gases; Gene Expression; Hippocampus (Brain); Human; Hyaluronan; Hydrogen; Image; Imaging Techniques; Imaging technology; Immunohistochemistry; Ions; Isomerism; Label; Light; Link; Liquid Chromatography; Maps; Mass Spectrum Analysis; Medial; Mediating; Metabolism; Middle frontal gyrus structure; Modernization; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neuronal Dysfunction; Neurons; Neuropeptides; Neurosciences; Pathogenesis; Pathologic; Pathology; Patients; Pattern; Peptides; Phase; Physiological; Polymers; Polysaccharides; Proteins; Reporting; Research; Resolution; Rodent; Role; Senile Plaques; Societies; Source; Spatial Distribution; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sulfate; Synapses; System; Tauopathies; Technology; Testing; Tissues; Toxic effect; Translating; Up-Regulation; abeta accumulation; abeta deposition; base; brain cell; brain tissue; dermatan sulfate chondroitin sulfate; design; disorder control; extracellular; genome-wide; hyperphosphorylated tau; imaging platform; insight; ion mobility; neurogenesis; neuron loss; neuropathology; novel; polysulfated glycosaminoglycan; relating to nervous system; response; spatial relationship; tandem mass spectrometry; targeted treatment; tau Proteins; tau aggregation; tau-1; therapeutic target

Alzheimer’s disease (AD) is a dementing disorder characterized by the pathological accumulation of beta- amyloid (Ab) and hyperphosphorylated tau neurofibrillary tangles (NFTs). Recent evidence suggests a close topographical relationship P-tau accumulation and neuronal loss with changes in gene expression mediating chondroitin sulfate (CS) and dermatan sulfate (DS) glycosaminoglycan (GAG) metabolism. CS/DS-GAGs are extracellular polyanionic polymers that have previously been shown to interact with P-tau and Ab, although the underlying molecular mechanisms and physiological consequences for these interactions remain unclear. Studies that investigate the relationship between changes in brain CS/DS-GAGs and AD-associated pathological endpoints are therefore necessary to elucidate a novel role for glycans in the clinical pathogenesis of AD. The biological functions of extracellular CS/DS-GAGs are highly influenced by the incorporation of sulfated disaccharide isomers (0S-, 4S-, 6S-, 2S6S-, 4S6S-CS and 2S4S-DS) into the glycan matrix lattices. Often referred to as the biological “sulfation code”, the relative abundance of non-, mono- and di-sulfated CS/DS isomers is believed to control ion buffering, protein-glycan interactions, and neurocircuit synapse stability in the brain. Using state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS/MS), our Preliminary Data show a significant increase in the relative abundance of glial scar-associated isomers (6S- and 4S6S-CS) within the medial frontal gyrus of patients with AD compared to non-AD controls. Moreover, these glial scar- associated CS isomers positively correlate with the abundance of P-tau from the same brain tissue, suggesting that changes in the brain CS/DS-GAG sulfation code could serve as a novel and unexplored player in the progression of AD. Specifically, we hypothesize that the increase in glial-scarring CS/DS-GAGs may represent 1) a physiological CNS barrier to isolate P-tau neuropathology from the healthy brain tissue and 2) a repressor of neurogenesis and source of cellular toxicity, potentially exacerbating neurodegeneration in AD. Here, we propose to uncover the spatial distribution of CS/DS isomers with the underlying cellular (neuronal, glial) and pathological (P-tau, Ab) tissue pathology by coupling matrix assisted laser desorption ionization (MALDI) mass spectrometry imaging (IMS) of CS/DS isomers with histochemical protein labeling using advanced High Definition Imaging (HDI) overlay technology. Deciphering a relationship between maladaptive changes in the brain CS/DS-GAG sulfation code and development of AD pathology is a novel and unexplored area of glycan- based neuroscience with the potential to revolutionize the field of AD research.

阿尔茨海默氏病（AD）是一种痴呆症，其特征是β- 淀粉样蛋白（AB）和高磷酸化的Tau神经原纤维缠结（NFTS）。最近的证据表明接近 地形关系P-TAU积累和神经元丧失，基因表达介导的变化 硫酸软骨素（CS）和皮肤硫酸盐（DS）糖胺聚糖（GAG）代谢。 CS/DS-GAG是 以前已证明与p-tau和AB相互作用的细胞外聚发电机聚合物，尽管 这些相互作用的基本分子机制和物理后果尚不清楚。 研究脑CS/DS-GAG和与AD相关病理学的变化之间的关系 因此，终点是阐明聚糖在AD临床发病机理中的新作用所必需的。 细胞外CS/DS-GAG的生物学功能受硫化的掺入高度影响 二糖异构体（0s-，4s-，6s-，2s6s-，4S6S-CS和2S4S-DS）进入聚糖基质晶格中。经常 被称为生物学“硫酸盐代码”，是非，单，单和硫化的CS/ds的相对抽象 据信异构体可以控制离子缓冲，蛋白质 - 聚糖相互作用和神经信仰突触稳定性 脑。使用最先进的液相色谱串联质谱法（LC-MS/MS），我们的初步 数据表明，神经胶质疤痕相关的异构体的相对丰度（6S-和4S6S-CS）显着增加 与非AD对照组相比，在AD患者的额叶中间回旋中。而且，这些神经胶质疤痕 - 相关的CS异构体与从同一脑组织中的P-TAU的抽象呈正相关，这表明 大脑CS/DS-GAG硫酸盐代码的变化可能是一名新颖而出乎意料的玩家 AD的进展。特别是，我们假设CS/DS-GAG的Glial scarrial-scarrags-gag可能代表 1）物理中枢神经系统屏障与健康脑组织分离P-TAU神经病理学和2）复制品 神经发生和细胞毒性的来源，AD中可能加剧神经退行性。在这里，我们 提议揭示具有基础细胞（神经元，神经胶质）和的CS/DS异构体的空间分布 病理（P-TAU，AB）组织病理学通过耦合基质辅助激光解吸电离（MALDI）质量 使用先进的高高标记具有组织化学蛋白标记的CS/DS异构体的光谱成像（IMS） 定义成像（HDI）覆盖技术。解密适应不良变化之间的关系 脑CS/DS-GAG硫酸一件和AD病理学的发展是聚糖的新型且出乎意料的领域 基于神经科学，有可能改变广告研究领域。