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Lipidome and proteome of astrocyte and microglia ApoE lipoprotein reveal differences based on cell type and ApoE isoform.

Strickland MR, Wang Z, Golden LR, Wang H, Lu P et al.
J Lipid Res 2026
Open on PubMed

Apolipoprotein E (ApoE) is the primary, most abundant apolipoprotein of the 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 AD. 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 the ApoE isoform. Lipidomics revealed that microglia-derived ApoE lipoproteins were enriched in cholesteryl esters, whereas astrocyte ApoE lipoproteins were enriched in SM. Proteomics revealed that 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 complement component 1q and Lpl compared with ApoE2 and ApoE3 microglial lipoproteins, which were enriched in Ankk1 (ankyrin repeat and kinase domain containing 1) and apolipoprotein C1. 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.

14 Figures Extracted
Fig. 1
Fig. 1 PMC
A: Schematic showing workflow for purification of intact ApoE lipoprotein particles, followed by proteomic and lipidomic analyses. Primary glia were f...
Fig. 2
Fig. 2 PMC
A: Volcano plot showing enrichment of lipid species of astrocyte immunopurified lipoprotein versus microglia immunopurified lipoprotein. Microglia Apo...
Fig. 3
Fig. 3 PMC
A: Histogram of the most abundant proteins measured in astrocyte ApoE lipoproteins. Abundance was determined by excluding common contaminants, showing...
Fig. 4
Fig. 4 PMC
A: Histogram of the most abundant proteins measured in microglia ApoE lipoproteins. Abundance was determined by excluding common contaminants, showing...
Fig. 5
Fig. 5 PMC
A: Volcano plot showing differential protein abundance of proteins bound to astrocyte versus microglia immunopurified lipoprotein. Proteins involved i...
Fig. 6
Fig. 6 PMC
A: Volcano plot showing decreased CE species in ApoE lipoproteins immunopurified from T0901317-treated astrocyte-conditioned media compared to ApoE li...
Fig. 7
Fig. 7 PMC
A: Purity of astrocyte cultures is demonstrated by positive staining of GFAP, an astrocyte marker, and negative staining for Iba1, a microglial marker...
Fig. 8
Fig. 8 PMC
A: Representative images of Lpl staining in ApoE3 and ApoE4 knock-in mice frontal cortical sections. Astrocytes are stained using the astrocyte marker...
Figure S1
Figure S1 PMC
A: Volcano plot showing enrichment of lipid species of microglia ApoE2 immunopurified lipoprotein (n=4) versus microglia ApoE3 immunopurified lipoprot...
Figure S2
Figure S2 PMC
A: Venn diagram showing overlap of all proteins identified as being significantly enriched in the astrocyte ApoE proteome, microglia ApoE proteome, th...
Figure S3
Figure S3 PMC
A: Histogram of most abundant proteins measured in astrocyte ApoE2 lipoproteins (n=5). Abundance was determined by excluding common contaminants, show...
Figure S4
Figure S4 PMC
A: Histogram of the most abundant proteins measured in microglia ApoE2 lipoproteins (n=3). Abundance was determined by excluding common contaminants, ...
Figure S5
Figure S5 PMC
A: Volcano plot showing differential protein abundance of proteins bound to astrocyte ApoE2 (n=5) vs. microglia ApoE2 (n=3) immunopurified lipoprotein...
Figure S6
Figure S6 PMC
A: Representative images of Lpl staining in APPPS1-ApoE3 and APPPS1-ApoE4 knock-in mice frontal cortical sections. Astrocytes are stained using the as...
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