Fragmentation of apolipoprotein E4 is required for differential expression of inflammation and activation related genes in microglia cells

This study assessed the effects of the full-length ApoE4 protein on modulating the transcriptome of BV2 microglial cells and comparing to a previous report looking at an amino-terminal fragment of ApoE4 (residues 1-151). The results indicated that full-length ApoE4 had a very small effect on gene expression compared to the fragment. Only 48 differentially expressed genes (DEGs) were identified (p<0.05, and greater than 2-fold change). A gene ontology analysis of these DEGs indicated that they are not involved in inflammatory and activation processes, in contrast to the genes upregulated by the E4-fragment. In addition, genes that showed a negative fold-change upon FL-E4 treatment typically showed a strong positive fold-change upon treatment with the fragment (Pearson’s r=-0.7). Taken together, these results support the hypothesis that a key step in the conversion of microglia to an activated phenotype is proteolytic cleavage of FL-ApoE4. Therefore, the neutralization of this amino-terminal fragment of ApoE4, specifically, may serve as an important therapeutic strategy in the treatment of AD. Total RNA-sequencing was performed to assess transcriptional changes that occurred in BV2 microglial cells following treatment with human full-length ApoE4