Date of Award

12-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Neurobiology of Aging

Department

Graduate School of Biomedical Sciences

First Advisor

Meharvan Singh

Abstract

Women make up nearly two thirds of total Alzheimer’s cases in the United States. It has been speculated that the loss of endogenous estradiol during menopause is, at least in part, what renders the post-menopausal brain more vulnerable to the effects of aging and Alzheimer’s Disease. While hormone therapy can potentially thwart some of the undesirable consequences and increased risks associated with menopause, women are increasingly rejecting hormone therapy and seeking alternative therapy. There is a strong in interest in phytoestrogens as an alternative to traditional hormone therapy.

Phytoestrogens are naturally occurring estrogen like compounds derived from plants which have been shown to have a variety of health benefits. Their effects in the brain however are not fully understood. It was my goal to evaluate the effect of phytoestrogens on brain cells as it relates to neuroprotection. We initially assessed the ability of genistein, the most abundant phytoestrogen found in soy, to protect brain cells against age-associated insults in vitro using the hippocampal cell line (HT22 cells), a cortical cell line (HCN-1A cells), and primary slice cultures of the cerebral cortex. The results of these experiments were such that genistein was protective in the explant model and HCN-1A cells, but not in the HT22 cells suggesting that certain key players must be present for genistein to elicit neuroprotective effects. Based on the known estrogen receptor (ER) profiles for the models used in our study, we hypothesized that ER profiles may dictate the effects of phytoestrogens on brain cells. As such, we evaluated male and female C57/Bl6 mice at 3 different ages for ER expression profile and the effects that a phytoestrogen diet had on BDNF, used in this study as a surrogate marker of neuroprotection. Results showed that phytoestrogens’ effects on the brain differ between the cortex and the hippocampus and are dependent upon the sex of the animal and age at which the diet was initiated. From our results we have proposed a mechanism by which phytoestrogens differentially elicit their effects in the brain. The data presented herein provides valuable insight into phytoestrogens’ effects on the brain.

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