Spatial-temporal lipidomics reveals dysregulated lipid metabolism in mouse brain during Alzheimer’s disease progression

INTRODUCTION: Tracking spatial lipidomic changes during Alzheimer's disease (AD) progression is crucial for elucidating the underlying mechanisms of the disease. OBJECTIVES: This study aims to investigate the spatial-temporal lipidomic alterations and their associated metabolic enzyme changes during AD progression. METHODS: The spatial lipidomic changes and corresponding alterations in metabolic enzymes during AD progression in amyloid precursor protein/presenilin-1 (APP/PS1) mice were thoroughly analyzed using an advanced ambient mass spectrometry imaging (MSI) technique, complemented by immunofluorescence (IF) imaging. RESULTS: Distinct lipidomic differences were observed between AD and wild-type (WT) mice in both the hippocampus (HP) and thalamus (TH), with the TH region exhibiting more significant lipid changes than the HP. A total of 88 lipid species with age- and region-specific alterations were identified, primarily within the sphingolipid, glycerolipid, and glycerophospholipid metabolic pathways. These metabolic changes were corroborated by IF imaging, which demonstrated spatial variations in the corresponding enzymes within the lipid metabolic pathways. Notably, a significant downregulation of hexosylceramides (HexCers) in the white matter of aged APP/PS1 mice suggests potential white matter abnormalities linked to AD. Correlation analysis further revealed that reduced HexCers were associated with the inhibited sulfatide-HexCer pathway, potentially driven by diminished ARSA levels, a factor known to be involved in microglial activation and inflammation. Additionally, upregulation of diacylglycerol (DG), observed even during the pre-symptomatic phase of AD, suggests DG as an early diagnostic biomarker. A strong correlation between the spatial changes in the DG-to-phosphatidylcholine (PC) ratio and phospholipase C (PLC) expression indicates that DG upregulation may result from PLC activation, a process known to be induced by amyloid β. CONCLUSIONS: This study provides an expanded spatial, temporal, and chemical perspective on AD mechanisms, offering potential avenues for enhancing early diagnosis and therapeutic strategies.