mRNA editing of the Alzheimer's risk gene APOE

Variants in the human APOE gene govern the risk of Alzheimer's disease and other disorders. Three major APOE variants in humans reflect C→T replacements at two positions in a single exon: an upstream variant (AE4 site) that differs between the ancestral APOE ε4 allele ( APOE4 ) (C) and human-specific APOE2 / E3 (T), and a downstream variant (AE2 site) that differentiates APOE3 / E4 (C)from APOE2 (T). It has long been assumed that APOE allelotypes are genomically encoded, but here we report that multiple individuals express brain APOE C or U/T variant transcripts that differ from genomically templated versions. We demonstrate up to 10% C→U or U→C nucleotide replacement at AE4 and AE2, but not at other sites, and with no corresponding changes in genomic DNA. Single-cell transcriptomic datasets from brain microglia revealed sporadic (up to ∼8%) C→U replacement at AE2. We found 0.4-1.6% of brain transcripts in human APOE knock-in mice harbor selective C→U changes at either AE4 or AE2 sites. Transfection of HepG2 or Huh7 cells with either mouse or human APOBEC1 led to efficient (>90%) C→U editing of APOE4 mRNA at the AE4 but not AE2 site, with lower (<10%) C→T editing of genomic DNA at the AE4 site by mouse, but not human, APOBEC1. Furthermore, interrogation of proteomic datasets revealed up to 4% of non-genomically encoded APOE peptides in human plasma, indicating that the edited APOE transcripts are functional in vivo . These data suggest that APOE mRNA is subject to RNA editing that interconverts the different allelic forms of APOE .

Human APOE gene variants govern the risk of Alzheimer's disease (AD) and other disorders. Three alleles are widespread: ancestral E4 and human-specific E3 and E2 . AD risk declines in the order E4 > E3 > E2 . It has been assumed that the APOE allotype we inherit is laid down at birth, but we report that APOE mRNA is enzymatically edited to convert E4 to E3 / E2 , and/or E2 to E3 / E4 . Up to ∼10% conversion was seen in brain, and up to 100% in vitro driven by the RNA-editing enzyme APOBEC1. Proteomic analysis of human plasma argues that edited APOE transcripts are functional in vivo .