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 Aβ
peptides and neuronal
lipids. We here developed a novel trimodal, high-resolution (10 μm) 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 μm) and with high spectral quality. This was followed by 10 μm 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 Aβ plaque-associated
lipids and Aβ
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 Aβ
isoforms (Aβ 1-37, Aβ 1-38, Aβ 1-40). This highlights the potential of IMS3 as an alternative, superior approach to consecutively performed immuno-based Aβ staining strategies. Furthermore, the IMS3 workflow allowed for multimodal in situ MS/MS analysis of both
lipids and Aβ
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.