Abstract：
Alzheimer\'s disease (AD) is a progressive neurological condition characterized by impaired cognitive function and behavioral alterations. While AD research historically centered around mis-folded proteins, advances in mass spectrometry techniques have triggered increased exploration of the AD lipidome with lipid dysregulation emerging as a critical player in AD pathogenesis. Gangliosides are a class of glycosphingolipids enriched within the central nervous system. Previous work has suggested a shift in a-series gangliosides from complex (GM1) to simple (GM2 and GM3) species may be related to the development of neurodegenerative disease. In addition, complex gangliosides with 20 carbon sphingosine chains have been shown to increase in the aging brain. In this study, we utilized matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) to interrogate the in situ relationship of a-series gangliosides with either 18 or 20 carbon sphingosine chains (d18:1 or d20:1, respectively) in the post-mortem human AD brain. Here, we expanded upon previous literature and demonstrated a significant decrease in the GM1 d20:1 to GM1 d18:1 ratio in regions of the dentate gyrus and entorhinal cortex in AD relative to control brain tissue. Then, we demonstrated that the MALDI-MSI profile of GM3 co-localizes with histologically confirmed amyloid beta (Aβ) plaques and found a significant increase in both GM1 and GM3 in proximity to Aβ plaques. Collectively, this study demonstrates a perturbation of the ganglioside profile in AD, and validates a pipeline for MALDI-MSI and classic histological staining in the same tissue sections. This demonstrates feasibility for integrating untargeted mass spectrometry imaging approaches into a digital pathology framework.
摘要：
阿尔茨海默病（AD）是一种进行性神经系统疾病，其特征是认知功能受损和行为改变。虽然AD研究历史上集中在错误折叠的蛋白质上，质谱技术的进步引发了人们对AD脂质组的更多探索,脂质失调成为AD发病机制中的关键角色.神经节苷脂是一类富含中枢神经系统的鞘糖脂。先前的工作表明，一系列神经节苷脂从复杂（GM1）物种向简单（GM2和GM3）物种的转变可能与神经退行性疾病的发展有关。此外,具有20个碳鞘氨醇链的复杂神经节苷脂已被证明在衰老的大脑中增加。在这项研究中,我们利用基质辅助激光解吸电离质谱成像(MALDI-MSI)研究了a系列神经节苷脂与18或20条碳鞘氨醇链(分别为d18:1或d20:1)在死后人类AD脑中的原位关系.这里,我们对以前的文献进行了扩展，并证明了相对于对照脑组织，AD中齿状回和内嗅皮层区域的GM1d20:1与GM1d18:1的比率显着降低。然后，我们证明GM3的MALDI-MSI谱与组织学证实的淀粉样蛋白β(Aβ)斑块共定位,并发现在Aβ斑块附近GM1和GM3均显著增加.总的来说，这项研究证明了AD中神经节苷脂轮廓的扰动，并在同一组织切片中验证MALDI-MSI和经典组织学染色的管道。这证明了将非目标质谱成像方法集成到数字病理学框架中的可行性。
