Multimodal Nano-DESI Mass Spectrometry Imaging Reveals Phospholipids Accumulation in and around Amyloid Plaques in Alzheimer’s Disease

Alzheimer's disease (AD), characterized by β-amyloid plaques, is increasingly recognized by lipid dysregulation as a key factor in its pathology. Mass spectrometry imaging (MSI), a powerful tool for mapping the spatial distribution of biomolecules in tissue sections, is ideally suited for investigating region-specific molecular alterations in diseased animal tissues. Recent MSI advancements have revealed plaque-associated molecular features in the AD brain, highlighting the role of metabolic dysfunction in disease progression. In this study, we developed a novel multimodal MSI approach using nanospray desorption electrospray ionization (nano-DESI) for dual polarity mode lipid and peptide imaging in the brain tissues of 5-7-month-old transgenic familial AD mice (5xFAD), followed by fluorescence imaging of β-amyloid plaques on the same tissue section. Our results revealed the accumulation of several peptides and phospholipids, including phosphatidylethanolamines (PE), phosphatidylinositols (PI), phosphatidylglycerols (PG), and phosphatidylcholines (PC) in and/or surrounding β-amyloid plaques in the hippocampus, isocortex, and thalamus regions of the AD brain. Furthermore, we observed that several fatty acids (FAs) were enhanced in the plaque-enriched subiculum region of the hippocampus. Our results demonstrate the power of the multimodal nano-DESI MSI approach for comprehensive mapping of molecular pathology with high spatial resolution, providing unique insights into disease metabolism and potential biomarkers.