Fragmentation of apolipoprotein E4 is required for differential expression of inflammation and activation related genes in microglia cells. 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. Overall design: Total RNA-sequencing was performed to assess transcriptional changes that occurred in BV2 microglial cells following treatment with human full-length ApoE4