The Sex-Specific Effects of Stress in Alzheimer’s Disease Mouse Models

Dominguez, Sky

doi:https://doi.org/10.21985/n2-zt83-be22

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The Sex-Specific Effects of Stress in Alzheimer’s Disease Mouse Models

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As of 2020, there are currently 5.8 million people in the United States suffering from Alzheimer’s Disease (AD), a debilitating and progressive neurodegenerative disorder. Of these nearly six million people, two-thirds are women. While it has been suggested that women’s longer lifespan accounts for this disparity, the overall lifetime risk for Alzheimer’s dementia is nearly two times greater for women than men at the age of 65, and, further, this risk divergence is purported to exist even at the age of 45. This suggests that there are other factors contributing to the increased risk of AD in women, whether that be biological mechanisms or increased vulnerability to other risk factors. One other such risk factor is that of stress. Preclinical studies have shown that stress paradigms can increase the biological and behavioral markers associated with AD progression. Moreover, clinical studies have found a correlation between reported stress levels or measured biochemical markers of stress and disease severity. The sex-disparity in disease prevalence seen in AD has also been reported in other disorders where stress is a major contributor, such as major depressive disorder. This all supports the theory that women may be more or differently affected by stress and thus more vulnerable to stress-linked pathology including AD. To date, there remains a lack of studies that look at the interaction between sex, stress, and AD. More studies are needed to clarify how the interaction of these factors affects AD progression. The aim of this thesis is to characterize the effect of stressor type, length of stress, timing of stress, and AD model for both male and female mice. In attempts to reach this goal, the following four experimental studies were conducted. In Study 1, behavioral data collected from young, 5-month-old, APP-PS1 mice with and without exposure to a Chronic Unpredictable Mild Stress (CUMS) stress paradigm were analyzed. CUMS began when mice were 4 months of age and lasted 4 weeks, with behavioral testing beginning after two weeks of stress. Brain samples were then sent for proteomic and phosphoproteomic testing to allow for the analysis of differences in protein and phosphoprotein expression between unstressed and stressed male and female AD mice. This study found that there were no significant behavioral findings and no differences in protein expression between unstressed-stressed males or females, but that there were significant sex-specific differences in phosphoprotein expression in response to stress. Study 2 looked at the effect of acute restraint stress on 7-month-old APP-PS1 and WT mice of both sexes. Acute restraint stress was conducted for 2 hours, 30 minutes prior to each behavioral assessment with 5 days between each assessment. Analysis of behavioral data found no significant results for the interaction of sex-stress-genotype, with varied results for single effects such as only an effect of stress. Study 3 used a single 24-hour restraint stress paradigm on 12-month-old 5xFAD and WT mice, male and female. Behavioral assessments were then conducted two days after the end of stress. Analysis found once again varied results, with some tests showing not only an effect of stress but also sex-differences, while other behavioral assessments showed only an effect of the 5xFAD genotype or no effect at all. Finally, in Study 4, male and female 5xFAD mice were either group-housed or socially isolated in single-housed caging without enrichment beginning at wean-age (21-24-days-old). At 12 months of age, these mice along with group-housed wild-type (WT) littermates underwent a series of behavioral assessments. The analysis of these behaviors had varied results in terms of anxiety- and depressive-like symptoms, with no effect on measurements of memory as a result of stress in either sex. Overall, these results demonstrate that stress exacerbates some aspects of the Alzheimer’s phenotype in mice without any differences in the effects of stress between males and females. However, stress did alter affective behavior more in females compared to males and exerted sex-specific effects on phosphopeptide expression. These findings demonstrate the importance of experimental design, choice of mouse model, and timing of proposed experiments in the discernment of the interactions between the factors noted (i.e., sex, stress, and AD-like pathology).

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