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

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. Changes in lipid compositions have been reported in AD using targeted mass spectrometry approaches and connected to neuroinflammation but provided limited spatial detail. We report here a new non-targeted approach for discovering and mapping region-specific, plaque-associated lipids including isomers. We accomplish this via a multimodal framework that integrates matrix assisted laser desorption/ionization with laser-induced postionization (MALDI-2) mass spectrometry imaging and trapped ion mobility spectrometry-based spatial lipidomics. Our approach integrates significantly enhanced detectability and spatial-chemical resolution, fluorescence microscopy, and a computational pipeline for multimodal image co-registration and untargeted discovery of plaque-altered lipids. Plaque-associated and brain-region-specific lipidomic changes with striking lipid heterogeneity among individual Aβ plaques across different regions were revealed, as well as unique spatial distributions of lipid isomers around Aβ plaques in a mouse AD model. This approach provides a new tool to enhance our understanding of the Aβ microenvironment.