MALDI imaging of glial scar-forming glycans in Alzheimers disease

阿尔茨海默病(AD)是一种痴呆障碍，其特征是β-淀粉样蛋白的病理性堆积。 淀粉样蛋白(Ab)和过度磷酸化的tau神经原纤维缠结(NFTs)。最近的证据表明， P-tau堆积和神经元丢失与基因表达变化的地形学关系 硫酸软骨素(CS)和硫酸皮肤素(DS)糖胺聚糖(GAG)代谢。CS/DS-GAG是 以前被证明与P-tau和Ab相互作用的细胞外多阴离子聚合物，尽管 这些相互作用的潜在分子机制和生理后果尚不清楚。 探讨脑CS/DS-GAG变化与AD相关病理关系的研究 因此，对于阐明多糖在阿尔茨海默病临床发病机制中的新作用，终点是必要的。 硫酸盐的掺入对胞外CS/DS-GAGS的生物学功能有很大影响 二糖异构体(0S-、4S-、6S-、2S6S-、4S6S-CS和2S4S-DS)进入多糖基质晶格。经常 非、单硫化和双硫化CS/DS的相对丰度被称为生物“硫化代码” 异构体被认为控制着离子缓冲，蛋白质-多糖相互作用，以及神经回路突触的稳定性 大脑。使用最先进的LC-MS/MS(LC-MS/MS)，我们的初步 数据显示，胶质瘢痕相关异构体(6S-和4S6S-CS)的相对丰度显著增加 阿尔茨海默病患者额叶内侧回与非阿尔茨海默病患者比较。此外，这些神经胶质疤痕- 相关的CS异构体与同一脑组织中P-tau的丰度呈正相关，提示 脑中CS/DS-Gag硫酸盐化代码的变化可能会在 AD的进展。具体地说，我们假设胶质瘢痕形成的CS/DS-GAG的增加可能代表 1)从健康脑组织分离P-tau神经病理的生理中枢神经系统屏障和2)抑制物 神经发生和细胞毒性的来源，可能加剧阿尔茨海默病的神经变性。在这里，我们 建议揭示CS/DS异构体的空间分布和潜在的细胞(神经元、神经胶质)和 耦合基质辅助激光解吸电离(MALDI)的病理组织病理学 高级高级组织化学蛋白质标记CS/DS异构体的光谱成像 清晰度成像(HDI)覆盖技术。破译不适应变化之间的关系 脑CS/DS-Gag硫酸盐化密码与AD病理的发展是一个新的和未被探索的领域-- 以神经科学为基础，有可能给AD研究领域带来革命性的变化。

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.