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. We report here a new approach for discovering and mapping 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-based spatial lipidomics and fluorescence microscopy. Our approach offers significantly enhanced detectability and spatial-chemical resolution, and a computational pipeline for multimodal image co-registration and discovery of plaque-altered lipids. Here, we present a method to reveal plaque-associated and brain-region-specific lipidomic changes with striking heterogeneity among individual Aβ plaques across and within different regions. 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 both a powerful analytical framework and new biological insight into lipid alterations within the Aβ plaque microenvironment.