PR002547 (Project)

Description:Abnormal lipid metabolism is observed in Alzheimer’s disease (AD), but its contribution to disease progression remains unclear. Genetic studies indicate that microglia, the brain’s resident immune cells, influence lipid processing during AD. Here we show that, in both mouse models of AD and human postmortem brain tissue, microglia regulate the accumulation of specific lipids associated with disease pathology. Using multidimensional mass spectrometry-based shotgun lipidomics and histological analysis, we find that arachidonic acid-containing bis(monoacylglycero)phosphate (BMP) accumulates in response to amyloid plaques, and this buildup depends on microglial function and the AD risk gene progranulin (GRN). In contrast, lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) accumulate independently of microglia, instead associating with astrocyte activation and oxidative stress. These findings connect dysregulated lipid metabolism in AD to distinct brain cell types and molecular pathways. The results suggest that microglial regulation of lipid homeostasis is a potential therapeutic target for AD.