Interaction between sex and apolipoprotein e genetic background in a murine model of intracerebral hemorrhage

Abstract

Emerging evidence suggests sex and apolipoprotein E (APOE) genotype separately modify outcomes after intracerebral hemorrhage (ICH). We test the hypothesis that an interaction exists between sex and APOE polymorphism in modifying outcomes after ICH and is altered by administration of exogenous apoE-mimetic peptide. To define the effects of sex and APOE polymorphism in ICH, we created collagenase-induced ICH in male and female APOETR mice (targeted replacement mice homozygous for APOE3 or APOE4 alleles; n=12/group) and assessed performance on Rotarod (RR) and Morris water maze (MWM). To evaluate hematoma formation, we used hematoxylin and eosin staining at 24 h after injury (n=8/group). Using separate cohorts (n=12/group), apoE-mimetic peptide (COG1410 at 2 mg/kg) was administered after ICH, and mice were assessed by RR and MWM. Female mice outperformed male mice via RR and MWM by over 190% improvement through 7 days (RR) and 32 days (MWM) of testing after ICH (p<0.01). Female APOE3TR mice demonstrated improved function compared with all other groups (p<0.05) without any difference in hematoma volume at 24 h after injury in any group. Administration of a therapeutic apoE-mimetic peptide improved RR latencies through 7 days after ICH in male and female APOE4TR mice and MWM latencies over days 28-32 after ICH in male APOE4TR mice (p<0.05). Sex and APOE polymorphism influence functional outcomes in our murine model of ICH. Moreover, administration of exogenous apoE-mimetic peptide after injury differentially modifies the interaction between sex and APOE polymorphism.

Keywords: Apolipoprotein E; Female; Intracerebral hemorrhage; Murine; Sex differences.

Fig. 1

RR (a) and MWM (b) latencies in male and female APOETR mice after injury with ICH. Female APOE3TR animals improve to a greater degree than other groups of animals with male APOE4TR animals demonstrating the poorest short- and long-term neurobehavio-ral outcomes. Reference sham animals are denoted by the dotted line

Fig. 2

RR (a) and MWM (b) latencies in male and female APOETR mice after injury with ICH. Treatment with COG1410 improved the RR and MWM performance in female and male APOE4TR animals

Fig. 2

RR (a) and MWM (b) latencies in male and female APOETR mice after injury with ICH. Treatment with COG1410 improved the RR and MWM performance in female and male APOE4TR animals