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

## TL;DR

This study compares the lipid and protein content of ApoE lipoproteins from astrocytes and microglia, showing differences based on cell type and ApoE isoform, which may influence Alzheimer's disease risk.

## Contribution

The study reveals distinct lipid and protein profiles of ApoE lipoproteins based on their cellular origin and ApoE isoform, offering new insights into their roles in CNS function and disease.

## Key findings

- Microglia-derived ApoE lipoproteins are enriched in cholesteryl esters, while astrocyte-derived ones are enriched in sphingomyelin (SM).
- ApoE4 microglial lipoproteins show enrichment in complement component 1q and Lpl, whereas ApoE2/3 lipoproteins are enriched in Ankk1 and apolipoprotein C1.
- Astrocyte ApoE lipoproteins are associated with glucose metabolism and acute phase response proteins, while microglial ones are linked to immune and synapse-related functions.

## Abstract

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.