Simple gangliosides co-localize with amyloid plaques and increase with age in a transgenic mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease accounting for two-thirds of all dementia cases, and age is the strongest risk factor. Beyond the amyloid hypothesis, lipid dysregulation is now recognized as a core component of AD pathology. Gangliosides are a class of membrane lipids of the glycosphingolipid family and are enriched in the central nervous system (CNS). Ganglioside dysregulation has been implicated in various neurodegenerative diseases, including AD, but the spatial distribution with respect to amyloid-beta (Aβ) deposition is not well understood. To address this gap, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was employed to investigate the age-dependent expression profile of A-series ganglioside species GD1a, GM1, GM2, and GM3 in the APP/PS1 transgenic mouse model of AD that develops age-dependent amyloid-beta (Aβ) plaques. This study utilized a dual resolution approach combining whole brain imaging for comprehensive detection of ganglioside expression across neuroanatomical regions with high-resolution imaging of the cerebral cortex and hippocampus to interrogate plaque-associated ganglioside alterations. Results showed age-dependent changes in the complex gangliosides GM1 and GD1a across white and grey matter regions in both wildtype and APP/PS1 mice. Significantly higher levels of simple gangliosides GM2 and GM3 were observed in transgenic mice at 12 and 18 months compared to age-matched controls in the cortex and dentate gyrus of the hippocampus. Accumulation of GM3 co-localized with Aβ plaques in the aged APP/PS1 mice, and correlated with Hexa gene expression supporting ganglioside degradation as a mechanism for the accumulation of GM3 This work is the first to demonstrate that age-related ganglioside dysregulation is spatiotemporally associated with Aβ plaques using sophisticated MSI and reveals novel mechanistic insights underlying lipid regulation in AD.