Effects of APOE genotype and estrogen status on brain transcriptome in female mice.

Abstract

The predominant genetic risk factor for late-onset Alzheimer's disease (AD) is the ε4 allele of apolipoprotein E (APOE4). APOE4-related risk of developing AD is modified by sex, with women showing greater risk than men. Regardless of APOE genotype, women exhibit a higher prevalence and lifetime risk of AD. Extensive human and animal model literatures indicate that women's risk for AD is also affected by the normal, age-related depletion of estrogens at menopause. For example, in mouse models, estrogen depletion by ovariectomy accelerates the onset and progression of AD-like neuropathology and cognitive impairment, whereas estrogen-based hormone therapies can partially prevent and or reverse these effects. Potential interactions between APOE4 genotype and estrogen status have not been well elucidated. To provide more insight into these issues, we conducted transcriptional analysis on hippocampi from adult female mice across APOE3 and APOE4 genotypes in the presence or absence of estradiol. At 18-22 weeks of age, female mice homozygous for knock-in of human APOE3 or APOE4 were bilaterally ovariectomized (OVX) or sham-OVX and immediately implanted with a subcutaneous silastic capsule containing either vehicle or 0.5% 17β-estradiol (E2). Four weeks following surgery and hormone treatment, hippocampi were harvested and processed for polyA-enriched RNA-seq. Transcripts were mapped to a cDNA library of the mouse genome using kallisto (0.46.1). DEseq2 (1.28.1) normalized fold-changes were then used to estimate differential gene expression among groups. RNA-seq analyses indicate significant differences in hippocampal transcriptional profiles across treatment groups. In particular, we found group differences in pathways related to synaptic integrity and plasticity, lipid metabolism and glucose metabolism. Interestingly, the strongest group differences were associated with APOE genotype whereas estrogen status yielded generally modest effects. Our results suggest that APOE genotype impacts the transcriptome in the female hippocampus to a larger degree than estrogen status. These findings provide novel insight into the independent and interactive neural effects of APOE4 and estrogen, which may provide opportunities for identification of therapeutic targets for AD.