Lipidomic Network Analysis Reveals Amyloid-β-Induced Lysosomal Lipid Accumulation in the Cortex and Hippocampus of 5xFAD Mice

The 5xFAD mouse model serves as a valuable experimental system for investigating Alzheimer’s disease (AD), specifically amyloid-beta (Aβ)-induced AD pathology. In this study, we explored temporal, regional, and sex-specific alternations in the lipidome within the cortex and hippocampus of 5xFAD mice. Our results revealed that lipid alternations become more pronounced with the progression of Aβ pathology in the cerebral cortex and hippocampus. These lipid changes were also more significant in the female mice, which exhibited more severe Aβ pathology than male mice. Through lipid network analysis, we identified AD-specific lipid coexpression network modules in both brain regions, marked by enriched lysosomal lipids such as BMP and GM3. Notably, this lipid profile was also observed in microglia cells overexpressing the Swedish mutant form of Aβ precursor protein (APPswe). Given the critical role of BMP in lysosomal lipid and membrane degradation, and the observed enhancement of GM3 accumulation under lysosomal inhibition in APPswe-transfected microglial cells, these findings suggest that Aβ-mediated microglial lysosomal dysfunction may contribute to AD progression. Overall, we discovered a previously unrecognized role of Aβ in dysregulating lysosomal lipid metabolism and highlighted the utility of lipidomics and network analysis as complementary approaches for elucidating disease mechanisms.