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.

阿尔茨海默病（AD）是一种痴呆性疾病，其特征在于β-淀粉样蛋白的病理性积累。 淀粉样蛋白（Ab）和过度磷酸化的tau神经元缠结（NFT）。最近的证据表明 P-tau蛋白积聚和神经元丢失与基因表达介导的变化的拓扑关系 硫酸软骨素（CS）和硫酸皮肤素（DS）糖胺聚糖（GAG）代谢。CS/DS-GAG是 细胞外聚阴离子聚合物先前已显示与P-tau和Ab相互作用，尽管 这些相互作用的潜在分子机制和生理后果仍不清楚。 研究了脑CS/DS-GAG变化与AD相关病理变化之间的关系， 因此，有必要通过终点来阐明聚糖在AD临床发病机制中的新作用。 CS/DS-GAGs的生物学功能受硫酸化修饰的CS/DS-GAGs的掺入的高度影响。 在一些实施方案中，将二糖异构体（0 S-、4S-、6S-、2S 6S-、4S 6S-CS和2S 4S-DS）引入聚糖基质晶格中。经常 称为生物“硫酸化代码”，非硫酸化、单硫酸化和二硫酸化CS/DS的相对丰度 异构体被认为控制离子缓冲、蛋白质-聚糖相互作用和神经回路突触稳定性。 个脑袋使用最先进的液相色谱串联质谱法（LC-MS/MS），我们的初步 数据显示胶质瘢痕相关异构体（6S-和4S 6S-CS）的相对丰度显著增加。 与非AD对照组相比，AD患者的内侧额回内。此外，这些神经胶质疤痕- 相关的CS异构体与来自相同脑组织的P-tau丰度正相关，表明 大脑CS/DS-糖胺聚糖硫酸化密码的变化可以作为一种新颖且未经探索的参与者。 AD的进展。具体来说，我们假设胶质瘢痕CS/DS-GAG的增加可能代表了 1)从健康脑组织中分离P-tau神经病理学的生理CNS屏障，和2）阻遏物 神经发生和细胞毒性的来源，可能加剧AD中的神经变性。这里我们 建议揭示CS/DS异构体的空间分布与潜在的细胞（神经元，神经胶质）和 通过耦合基质辅助激光解吸电离（MALDI）质量的病理学（P-tau，Ab）组织病理学 使用先进的高光谱成像技术，用组织化学蛋白质标记CS/DS异构体的光谱成像（IMS） 清晰度成像（HDI）覆盖技术。解读适应不良的变化之间的关系 脑CS/DS-GAG硫酸化编码和AD病理学的发展是一个新的和未探索的聚糖领域， 基于神经科学，有可能彻底改变AD研究领域。