Date of Award

December 2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Psychology

First Advisor

Karyn M Frick

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, yet its cause remains a mystery and no truly effective treatments exist. The high incidence of AD, coupled with its devastating health and economic impacts, highlight the urgent need for continued research into the etiology of this disease (Ernst & Hay, 1994; Rice et al., 1993). Although existing and efficacious treatments for AD are lacking, several risk factors for AD have been identified. One such factor is apolipoprotein E genotype, which is the greatest genetic risk factor for AD (Ertekin-Taner, 2007; van der Flier et al., 2011). Another factor is female sex; women comprise almost two-thirds of AD cases (Alzheimer’s Association, 2021), illustrating a need to understand whether there are sex and gender-specific risk factors for AD. Importantly, female sex acts synergistically with APOE4 genotype to increase disease risk (Altmann et al., 2014; Bretsky et al., 1999; Farrer et al., 1997). Considerable attention has been given to sex steroid hormones such as the potent estrogen 17-β estradiol (E2) as potential mediators of AD risk in females, especially given memory decline that coincides with the onset of the menopausal transition (Jacobs et al., 2016; Paganini-Hill & Henderson, 1996). However, interactions among sex, E2, and APOE genotype remain poorly characterized, both in human patients and in animal models of disease. The overall aim of this dissertation was to determine whether sex and estrogens influence memory consolidation and cognition, cell signaling, and dendritic morphology in a mouse model of AD designed to recapitulate APOE-associated disease risk. To this end, we used male and female transgenic mice that express 5 familial AD mutations (5xFAD) and human APOE3 (E3FAD) or APOE4 (E4FAD). We first tested 6 month-old male and female E3FAD and E4FAD mice in a behavioral battery of tasks including object recognition (OR), object placement (OP), open field (OF), and the Morris water maze, in order to assess whether female sex and APOE4 genotype act independently or together to increase anxiety-like behavior and interfere with memory consolidation. We then examined the brains of these mice to ask whether sex or APOE4 genotype, independently or concurrently, modulated changes in protein expression or dendritic spine density. Next, we asked whether gonadal status modulated anxiety-like behavior in female EFADs. Finally, we asked whether post-training intrahippocampal administration of E2 was of mnemonic benefit to female E3FADs, E3/4FADs, and E4FADs for object memory consolidation, and whether this treatment resulted in changes in protein expression or dendritic spine density in the brains of these mice. Collectively, our results suggest surprisingly few effects driven by sex alone, or interactions between sex and APOE4 genotype. However, APOE4 genotype was memory-impairing, associated with decreased spine density, and altered protein expression relative to APOE3 genotype. Furthermore, whereas E2 facilitated memory consolidation in ovariectomized E3FAD and E3/4FAD females, E4FAD females were resistant to the memory-enhancing effects of E2, including E2 -induced changes in dendritic spine density. Combined, these data add to a growing literature implicating APOE4 as a harmful risk factor for AD, and suggest that E2, and its downstream effectors, may be useful therapeutic targets for individuals not homozygous for APOE4.

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