Mechanisms of Estrogen Receptor Alternative Splicing and the Consequences for Aging in the Female Brain

The advances in healthcare and scientific knowledge have resulted in longer life expectancies in women. These advanced ages in women now means that they are experiencing the effects of age-related changes in the body for much longer periods of time, mainly reproductive senescence, resulting in the loss of circulating ovarian hormones. The age at which menopause occurs has not changed, resulting in women now living over a third of their lives in a postmenopausal state. The major circulating estrogen produced by the ovaries, 17β-estradiol (E2), has many homeostatic effects in the body like neuroprotection and cardioprotection. Hormone replacement therapy (HT) was to become the standard in treating women undergoing reproductive senescence in order to abrogate the negative effects associated with the decline in circulating E2, however adverse effects of HT were observed mainly women who were at least 10 years removed from menopause. These findings led to the idea of a therapeutic window in which ET is beneficial, known as the “timing hypothesis”, pointing to age-related adjustments that occur during and after this critical period of declining E2 levels. E2 is known to regulate transcription through an important class of nuclear steroid receptors called estrogen receptors (ERs). ERβ mediate the actions of E2 upon binding through interactions within the promoter region of ER-regulated genes and is subject to alternative splicing. It is through this process that ERβ splice variants arise altering the receptor function and responsiveness to E2 in the brain. These observations led to the hypothesis that aging and diminished E2 levels affect the alternative splicing of ERβ in the aged female brain through altered expression of ER-regulated splicing factors. ERβ alternative splice variants were measured in the brain of young and aged female rats who were subjected to increasingly longer periods of hormone deprivation. In vitro data from brain-derived cell lines also provided mechanistic answers to how ERβ is alternatively spliced in the brain. This dissertation work contributes to our overall understanding of ERβ in the context of its expression and possible function in the aging female brain