Multimodal mass spectrometry imaging for plaque- and region-specific neurolipidomics in Alzheimer’s disease mouse models

The progressive accumulation of amyloid beta (Aβ) plaques is a hallmark of Alzheimer’s disease (AD). However, the biochemical mechanisms of their formation and the consequences associated with plaque formation remain elusive. In female 5xFAD and APPNL-G-F mice, we map region-specific, plaque-associated lipids with large molecular coverage including isomers. We describe a multimodal framework that integrates matrix assisted laser desorption/ionization with laser-induced postionization (MALDI-2) mass spectrometry imaging, trapped ion mobility spectrometry, and fluorescence microscopy. Our approach improves detectability and spatial-chemical resolution. We couple these measurements with a computational pipeline for multimodal image coregistration and discovery of plaque-altered lipids. Here, we show the lipids in and around Aβ plaques are highly heterogeneous. Integration of our data with existing spatial transcriptomics data suggests that region-specific accumulation of simple gangliosides is likely driven by lysosomal degradation of complex species. Together, this work provides a generalizable framework to understand lipid alterations within the Aβ plaque microenvironment. Amyloid plaques are a hallmark of Alzheimer’s disease. Better understanding of their biochemistry can inspire new biomarkers and therapeutics. Using multimodal mass spectrometry imaging, this work reveals surprising lipid heterogeneity in plaque microenvironments across the brain.