Lipidoma y proteoma de lipoproteínas de ApoE de astrocitos y microglia revelan diferencias basadas en el tipo de...

Apolipoprotein E (ApoE) is the primary, most abundant apolipoprotein of the central nervous system (CNS) and plays an important role in brain metabolism and lipid homeostasis. In the CNS, ApoE is primarily secreted by astrocytes under homeostatic conditions and by microglia in certain disease-related conditions. APOE has three major alleles: APOE2, APOE3, and APOE4. APOE4 is the strongest genetic risk factor for late onset Alzheimer's disease (AD) and APOE2 results in decreased risk relative to APOE3. ApoE derived from astrocytes and microglia have been hypothesized to play different roles in the disease pathogenesis of Alzheimer's disease. In this study, we profiled the lipidome and proteome of ApoE lipoproteins secreted by astrocytes or microglia and found that they differed according to the cellular source of ApoE and ApoE isoform. Lipidomics revealed microglia-derived ApoE lipoproteins were enriched in cholesterol esters whereas astrocyte ApoE lipoproteins were enriched in sphingomyelin. Proteomics revealed astrocyte ApoE lipoproteins were enriched in proteins involved in glucose metabolism and acute phase response. Microglia-secreted lipoproteins were enriched in proteins involved in complement activation, synapse pruning, proteolysis, and the innate immune response. Further comparison of ApoE lipoproteins from APOE4 microglia revealed that ApoE4 lipoproteins were enriched in C1q and Lpl compared to ApoE2 and ApoE3 microglial lipoproteins which were enriched in Ankk1 and ApoC1. These results provide the molecular foundation for better understanding of how ApoE functions as an apolipoprotein with the lipoprotein cargo being dependent on the cellular source and ApoE isoform, ultimately contributing to CNS homeostasis and disease pathogenesis.