Title: The Triple Threat: Estrogen Deficiency, APOE Genotype, and Age on Cerebral Vascular Function
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Date
2025-02-24
Authors
Kehmeier, Mackenzie
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Publisher
University of Oregon
Abstract
As late-onset of Alzheimer’s disease (LOAD) prevalence increases, efforts toward elucidating mechanisms underlying LOAD pathology are needed. Three of the greatest genetic risk factors for late-onset Alzheimer’s disease are age, female sex, and the apolipoprotein E ε4 (E4) genotype. Two-thirds of LOAD cases are females, and perimenopause coincides with the prodromal phase of LOAD. Post-menopausal females with an E4 allele have higher rates of LOAD compared with age-matched males with an E4 allele, suggesting an interaction between APOE genotype, age, and estrogen deficiency. Cerebral endothelial function can alter cerebral blood flow (CBF) and compromise the blood-brain barrier. Cerebral endothelial dysfunction is a common link between the E4 genotype, estrogen deficiency, and LOAD. However, the interaction effect of APOE, age, and estrogen on cerebral endothelial cell function and mitochondrial health is unknown. I hypothesized that estrogen fluctuation and deficiency modulate cerebrovascular function, and this function is further impaired in the presence of the E4 genotype and age. The following aims were completed to test my hypotheses.
Aim 1: Determine the role of phytoestrogens and female sex hormones on cerebral vascular function. Aim 1 encompasses Chapters 2 & 3 of this dissertation and the main findings were two-fold. 1) The estrous cycle in female mice influenced large artery stiffness but not ex vivo endothelial function in resistance arteries. Thus, accounting for the estrous cycle for ex vivo endothelial function is not needed but should be accounted for when measuring in vivo large artery stiffness. 2) Phytoestrogens, specifically soy in the rodent diet, influenced cerebral vascular function, insulin signaling, and cognitive function. This study also confirmed previous findings that ovariectomy impairs endothelial function and, for the first time, demonstrated that a soy diet prevents adverse effects of ovariectomy on insulin-mediated vasodilation.
Aim 2: Determine the interaction effect of APOE genotype and estrogen deficiency on cerebral vascular function, in vivo whole-body metabolism, and ex vivo cerebral vascular mitochondrial health. The findings from Aim 2 are shown in Chapter 4. In E3 and E4 female mice, I investigated how estrogen deficiency influenced endothelial and mitochondrial function. Overall, these results indicated that APOE genotype modulates the impact of estrogen on the cerebrovasculature. 17β-estradiol enhanced cerebrovascular function and mitochondrial function in E3 mice, while E4 mice conferred resistance to estrogen status.
Aim 3: Determine the interaction effect of aging and APOE genotype on cerebral vascular and cognitive function. Aim 3 is addressed in Chapter 5, and investigated the influence of age and APOE genotype on vascular function and cognition. The major results of this study demonstrated that age has a greater influence on cerebral vascular function than the E4 genotype.
These series of studies highlight the importance of considering sex and age as a biological variable that can influence one’s results. The major novel finding of these studies is that the E4 allele confers resistance to estrogen status, and the broader impact of this finding is that consideration of APOE genotype is needed when prescribing hormone replacement therapy for menopausal females.
This dissertation includes previously published and co-authored material.
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Keywords
aging, apoe genotype, estrogen, sex differences, vascular function