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The Role of Neurosteroid Metabolites of Gonadal Steroid Hormones in Neuroprotection

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Title: The Role of Neurosteroid Metabolites of Gonadal Steroid Hormones in Neuroprotection
Author: Mendell, Ari Loren
Department: Department of Biomedical Sciences
Program: Biomedical Sciences
Advisor: MacLusky, Neil
Abstract: Gonadal steroid hormones are known to protect the brain against the development of neurodegenerative conditions, especially Alzheimer’s disease (AD). Women are approximately twice as likely to develop AD compared to men, which has been attributed to the drastic and abrupt decline of circulating ovarian steroid hormone levels that occurs around the time of menopause. Testosterone levels decline more gradually in aging men, which may account for the relative protection of the male brain. However, even the gradual age-related decline in circulating testosterone levels is associated with an increased risk for development of AD. Recent evidence has highlighted previously underappreciated protective roles of gonadal steroid metabolites that are synthesized in the brain. One such neurosteroid – 5α-androstane-3α,17β-diol (3α-diol) – is a metabolite of testosterone that may contribute to the effects of its precursor by acting through distinct cellular mechanisms. However, the possible neuroprotective functions of 3α-diol remain largely uncharacterized. The studies presented in this thesis explore these functions, with an emphasis on the protective role of 3α-diol in the prevention of AD-related pathology. Study 1 demonstrates that physiological concentrations of 3α-diol protect neurons against oxidative stress and AD-related toxicity in the form of amyloid β (Aβ) exposure in vitro, by inhibiting dysregulated ERK signaling, caspase-3 activation, and cell death. Study 2 demonstrates that 3α-diol and the progesterone-derived analog, allopregnanolone, differentially inhibit ERK phosphorylation induced by Aβ in the presence and absence of neurosteroid-sensitive gamma-aminobutyric acid type A (GABAA) receptors, suggesting an alternative, GABAA receptor-independent mechanism of action for 3α-diol. Study 3 demonstrates that the protective effects of 3α-diol against dysregulated ERK phosphorylation and associated neurotoxicity are dependent on modulation of the ERK-directed phosphatase, MKP3/DUSP6. Finally, study 4 demonstrates that inhibiting the synthesis of testosterone-derived neurosteroids in male 3xTg-AD mice impairs object recognition memory, dysregulates dendritic morphology, and exacerbates AD-related pathology and signaling dysfunction in the hippocampus. Collectively, the findings presented in this thesis characterize the neuroprotective effects of 3α-diol using both in vitro and in vivo models of AD, and suggest that this neurosteroid may play an important role in preventing the development of neurodegenerative disease.
URI: http://hdl.handle.net/10214/14723
Date: 2018-12
Rights: Attribution-NonCommercial-NoDerivatives 4.0 International
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Attribution-NonCommercial-NoDerivatives 4.0 International Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International