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

Abstract

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.

Serum metabonomics analysis of quercetin against the toxicity induced by cadmium in rats

“…[ 45 ] LysoPC also can induce neurotoxicity through oligodendrocyte demyelination and can promote neurotoxic protein aggregation. [ 46–50 ] LysoPC levels are drastically elevated in patients with brain injury. [ 51 ]…”

Chemical imaging of evolving amyloid plaque pathology and associated Aβ peptide aggregation in a transgenic mouse model of Alzheimer’s disease

“…In particular, matrix‐assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is a powerful, emerging technology for comprehensively delineating lipid, peptide and protein localizations in situ, while maintaining high chemical specificity (Hanrieder et al ; Hanrieder et al ; Michno et al ). In the context of AD, MALDI IMS has been demonstrated to be a powerful tool to measure Aβ peptide pattern in situ at single plaque resolution (Rohner et al ; Stoeckli et al ; Seeley and Caprioli ; Carlred et al ; Kaya et al ; Kakuda et al ; Michno et al ; Michno et al ; Michno et al ).…”

Mapping the fly Malpighian tubule lipidome by imaging mass spectrometry

“…Moreover, no noticeable signal intensity loss was found when compared with results from serial sections acquired in a single polarity at the same spatial resolution. Based on the work of Kaya et al, dual polarity IMS acquired at a 10‐μm spatial resolution may be possible without an offset . On the other hand, microdissected tubules were limited to 25‐μm spatial resolution because the multiple washing steps involved have led to a certain degree of species delocalization.…”