Chemical imaging of sphingolipids and phospholipids at the single amyloid-β plaque level in post-mortem human Alzheimer’s disease brain

Lipids dysregulations have been critically implicated in Alzheimer’s disease (AD) pathology. Chemical analysis of amyloid-β (Aβ) plaque pathology in transgenic AD mouse models has demonstrated alterations in the microenvironment in direct proximity to Aβ plaque pathology. In mouse studies, differences in lipid patterns linked to structural polymorphism among Aβ pathology, such as diffuse, immature, and mature fibrillary aggregate have also been reported. To date, no comprehensive analysis of neuronal lipids microenvironment changes in human AD tissue has been performed. Here, for the first time we leverage matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) though high speed and spatial resolution commercial time-of-light instrument, as well as high mass resolution in-house developed orbitrap system to characterize the lipid microenvironment in postmortem human brain tissue from AD patients carrying Presenilin 1 mutations (PSEN 1) that lead to familial forms of AD (fAD). Interrogation of the spatially resolved MSI data on a single Aβ plaque allowed us to verify nearly 40 sphingolipid and phospholipid species from diverse subclasses being enriched and depleted in relation to the Aβ deposits. This included monosialo-gangliosides (GM), ceramide monohexosides (HexCer), ceramide-1-phosphates (CerP), ceramide phosphoethanolamine conjugates (PE-Cer), sulfatides (ST), as well as phosphatidylinositols (PI), phosphatidylethanolamines (PE), and phosphatidic acid (PA) species (including Lyso-forms). Indeed, many of the sphingolipids species overlap with the species previously seen in transgenic AD mouse models. Interestingly, in comparison to the animal studies, we observed an increased localization of PE and PI species containing arachidonic acid (AA). These finding are highly relevant, demonstrating for the first time Aβ plaque pathology-related alteration in the lipid microenvironment in humans. They provide a basis for development of potential lipid biomarkers for AD characterization and insight into human-specific molecular pathway alterations.