New Publication from CeMOS: Exploring the Aβ Plaque Microenvironment in Alzheimer’s Disease Model Mice by Multimodal Lipid-Protein-Histology Imaging on a Benchtop Mass Spectrometer

Müller, E.; Enzlein, T.; Niemeyer, D.; von Ammon, L.; Stumpo, K.; Biber, K.; Klein, C.; Hopf, C. Exploring the Aβ Plaque Microenvironment in Alzheimer’s Disease Model Mice by Multimodal Lipid-Protein-Histology Imaging on a Benchtop Mass Spectrometer. Pharmaceuticals 2025, 18, 252. https://doi.org/10.3390/ph18020252

Abstract

Amyloid-β (Aβ) plaque deposits in the brain are a hallmark of Alzheimer’s disease (AD) neuropathology. Plaques consist of complex mixtures of peptides like Aβ_1–42 and characteristic lipids such as gangliosides, and they are targeted by reactive microglia and astrocytes. Background: In pharmaceutical research and development, it is a formidable challenge to contextualize the different biomolecular classes and cell types of the Aβ plaque microenvironment in a coherent experimental workflow on a single tissue section and on a benchtop imaging reader. Methods: Here, we developed a workflow that combines lipid MALDI mass spectrometry imaging using a vacuum-stable matrix with histopathology stains and with the MALDI HiPLEX immunohistochemistry of plaques and multiple protein markers on a benchtop imaging mass spectrometer. The three data layers consisting of lipids, protein markers, and histology could be co-registered and evaluated together. Results: Multimodal data analysis suggested the extensive co-localization of Aβ plaques with the peptide precursor protein, with a defined subset of lipids and with reactive glia cells on a single brain section in APPPS1 mice. Plaque-associated lipids like ganglioside GM2 and phosphatidylinositol PI38:4 isoforms were readily identified using the tandem MS capabilities of the mass spectrometer. Conclusions: Altogether, our data suggests that complex pathology involving multiple lipids, proteins and cell types can be interrogated by this spatial multiomics workflow on a user-friendly benchtop mass spectrometer.