Novel Trimodal MALDI Imaging Mass Spectrometry (IMS3) at 10 μm Reveals Spatial Lipid and Peptide Correlates Implicated in Aβ Plaque Pathology in Alzheimer's Disease
Novel Trimodal MALDI Imaging Mass Spectrometry (IMS3) at 10 μm Reveals Spatial Lipid and Peptide Correlates Implicated in Aβ Plaque Pathology in Alzheimer's Disease
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DOI：
10.1021/acschemneuro.7b00314
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发表时间：
2017-12-01
影响因子：
5
通讯作者：
Hanrieder, Jorg
中科院分区：
文献类型：
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作者：
Kaya, Ibrahim;Brinet, Dimitri;Hanrieder, Jorg
使用基质辅助激光解吸/电离质谱仪(MALDI-MS)的多模式化学成像可以在相同的组织切片中原位提供全面的分子信息。这对于研究阿尔茨海默病(AD)等不同的大脑病理是有意义的，最近的数据表明共定位Aβ多肽和神经元脂质具有关键的相关性。我们开发了一种新的三模式、高分辨率(10微米)MALDI成像MS(IMS)范式，用于在同一组织切片上进行负离子和阳离子模式脂质分析以及随后的蛋白质离子成像。1，5-二氨基萘(1，5-DAN)的基质升华使双极性脂质MALDI IMS在相同的像素点上具有高空间分辨率(10微米)和高光谱质量。然后在同一测量区域进行10微米分辨率的蛋白质成像，这使得脂肪信号与小鼠大脑不同小脑区域内的蛋白质分布模式相关联。三模式成像策略(IMS3)进一步被证明是一种同时探测18月龄转基因AD小鼠(TgArcSwe)海马区Aβ斑块相关脂质和Aβ多肽的有效方法。在此，IMS3揭示了不同脂质物种的强烈共存，包括神经酰胺、磷脂酰肌醇、硫脂(Cer 18：0，PI 38：4，ST 24：0)和溶血磷脂酰胆碱(LPC 16：0，LPC 18：0)与斑块相关的Aβ亚型(Aβ1-37，Aβ1-38，Aβ1-40)。这突出了IMS3作为连续进行的基于免疫的Aβ染色策略的一种替代的、更好的方法的潜力。此外，IMS3工作流程允许对脂类和Aβ多肽进行多模式原位MS/MS分析。总之，本文介绍的IMS3方法在具有高化学特异性的细胞长度尺度上的组织学特征的全面、高分辨率分子分析方面显示出巨大的潜力。因此，它为探索以神经毒性蛋白聚集为特征的神经退行性疾病的复杂分子病理提供了一种强有力的方法。
Multimodal chemical imaging using matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS) can provide comprehensive molecular information in situ within the same tissue sections. This is of relevance for studying different brain pathologies such as Alzheimer's disease (AD), where recent data suggest a critical relevance of colocalizing A beta peptides and neuronal lipids. We here developed a novel trimodal, high-resolution (10 mu m) MALDI imaging MS (IMS) paradigm for negative and positive ion mode lipid analysis and subsequent protein ion imaging on the same tissue section. Matrix sublimation of 1,5-diaminonaphthalene (1,5-DAN) enabled dual polarity lipid MALDI IMS on the same pixel points at high spatial resolutions (10 mu m) and with high spectral quality. This was followed by 10 mu m resolution protein imaging on the same measurement area, which allowed correlation of lipid signals with protein distribution patterns within distinct cerebellar regions in mouse brain. The demonstrated trimodal imaging strategy (IMS3) was further shown to be an efficient approach for simultaneously probing A beta plaque-associated lipids and A beta peptides within the hippocampus of 18 month-old transgenic AD mice (tgArcSwe). Here, IMS3 revealed a strong colocalization of distinct lipid species including ceramides, phosphatidylinositols, sulfatides (Cer 18:0, PI 38:4, ST 24:0) and lysophosphatidylcholines (LPC 16:0, LPC 18:0) with plaque-associated A beta isoforms (A beta 1-37, A beta 1-38, A beta 1-40). This highlights the potential of IMS3 as an alternative, superior approach to consecutively performed immuno-based A beta staining strategies. Furthermore, the IMS3 workflow allowed for multimodal in situ MS/MS analysis of both lipids and A beta peptides. Altogether, the here presented IMS3 approach shows great potential for comprehensive, high-resolution molecular analysis of histological features at cellular length scales with high chemical specificity. It therefore represents a powerful approach for probing the complex molecular pathology of, e.g., neurodegenerative diseases that are characterized by neurotoxic protein aggregation.