Spatial Mapping of Gangliosides and Proteins in Amyloid Beta Plaques at Cellular Resolution Using Mass Spectrometry Imaging and MALDI‐IHC

In pharmaceutical research and development, technologies like mass spectrometry imaging (MSI) offer spatially resolved compound distributions to aid in the discovery of drug targets and development of drug candidates. Through traditional and immunohistochemical approaches centered around MSI, distributions of endogenous lipids and proteins can be mapped on the same tissue section at cellular resolution. To highlight the cellular resolution capability of the integrated MSI workflow leveraged here, an animal model of Alzheimer's disease (AD) was interrogated due to the relationship of lipid dysregulation and extracellular protein deposition in driving disease pathology, especially at the site of amyloid beta (Aβ) plaques. Gangliosides, Aβ peptides, and microglia were imaged at 5 μm spatial resolution in the brains of an APPPS1 mouse model. GM3 and GM2 gangliosides displayed plaque-associated accumulation as supported by previous studies of a range of AD models. Advanced methods for achieving cellular resolution imaging of lipids and proteins have revealed heterogeneity in molecular distributions, which appears to be influenced by the microenvironment surrounding Aβ plaques. While these data could support future biological conclusions of AD, a central aim of this study was to emphasize the potential impact of an MSI workflow, which fuses spatial lipidomic and proteomic data at cellular resolution, on translational drug discovery research. This dual molecular imaging approach and data mining strategy can not only support efforts in the discovery of novel drug targets, but also in evaluating drug-target engagement when the distribution of a small molecule drug is simultaneously investigated.