Basic Science and Pathogenesis.

Background: Postmenopausal females who carry an APOE4 allele are at higher risk of late-onset Alzheimer's Disease (LOAD) compared to age-matched APOE4 males. Estrogen deficiency predisposes females to an increased risk of vascular, cognitive and metabolic impairments. Estrogen and APOE genotype are known to impact metabolic and mitochondrial function in the brain, but their effects on cerebral vessels are unknown. Thus, the purpose of this study was to determine the interaction between APOE genotype and estrogen deficiency in relation to cerebrovascular mitochondrial function.

Method: Young female homozygous APOE3 and APOE4 mice (n = 6-8 per group; 6 months old) fed a high-fat diet were ovariectomized ("ovx"), ovariectomized and supplemented with 17β-estradiol (0.36 mg, 60-day release, "estradiol"), or left intact ("sham"). At 2 months after ovariectomy, a glucose tolerance test (GTT) was performed, then cerebral arteries and arterioles were dissected, incubated in saponin, then assessed for mitochondrial respiration in response to substrates probing carbohydrate metabolism (Oroboros). Data are presented as mean±SEM.

Result: There was an interaction between APOE genotype and ovx/estradiol status in relation to cerebrovascular complex I (CI)- (p = 0.04) and complex II (CII)-coupled respiration (p = 0.04). Additionally, there was a significant effect of genotype, such that vessels from APOE3 mice had greater CI-coupled respiration than vessels from APOE4 mice (p = 0.02). When examining differences between APOE3 groups, APOE3-estradiol mice had a 53% greater CI-coupled respiration than APOE3-sham mice (15.4±3.4 vs. 7.2±1.2 pmol/(s*mg), p = 0.03) and a 60% greater CI-coupled respiration than APOE3-ovx mice (6.2±1.6 pmol/(s*mg), p = 0.007). The APOE3-estradiol group also had greater CI+CII-coupled respiration compared to both APOE3-sham (50.8±7.1 vs. 27.3±1.7 pmol/(s*mg), p = 0.006) and ovx groups (28.0±5.7 pmol/(s*mg), p = 0.009). Interestingly, CI and CI+CII coupled respiration did not differ between sham, ovx, and estradiol in APOE4 mice (p>0.05). Maximal uncoupled respiration was greater in the APOE3 mice than APOE4 mice (p = 0.01). Whole-body glucose tolerance did not differ between groups (all p>0.05).

Conclusion: Overall, these results indicate that APOE genotype modulates the impact of estrogen on the cerebrovasculature. We found that 17β-estradiol enhances cerebrovascular mitochondrial function in APOE3 mice but not APOE4 mice. The results suggest that estradiol supplementation may have more therapeutic benefit for APOE4 non-carriers.