Abstract

Alzheimer’s Disease (AD) is a neurodegenerative disease hallmarked by the presence of amyloid- plaques and tau tangles in the brain. The process of the disease begins decades prior to the onset of symptoms and is thought to be driven first by a buildup of amyloid- peptide in the extracellular space, triggering a cascade of pathology and symptomology culminating in loss of cerebral volume and cognitive impairment. Women are diagnosed with AD at a rate 2/3 higher than their male counterparts, even when controlling for age. While most driving factors of the disease are thought to be genetic, roughly 40% of disease risk is tied to modifiable risk factors. These risk factors include obesity, traumatic brain injury, sleep, and most interestingly, stress. Women are also more likely to develop stress related disorders, such as depression, post-traumatic stress disorder, and anxiety. Additionally, past trials that examine the role of hormone replacement therapy (HRT) in protecting cognition during aging have yielded conflicting results, suggesting there are different impacts of the various factors surrounding HRTs roll in the prevention of AD. We aim to elucidate the role of stress in the pathogenesis of AD, as well as the role of hormone signaling in female animals, to understand the impact these potentially modifiable risk factors have on disease. We find that there is a differential relationship between estrogen and progesterone signaling in female animals, with estrogen leading to an increase in amyloid- and progesterone leading to a decrease in amyloid-, suggesting that each hormone plays a different part in protecting brain health, and that an estrogen only approach to HRT may not be helpful in the prevention of AD. To further understand the impact of modifiable risk factors, we aimed to uncover the role of stress in amyloid- and tau kinetics. Using in vivo microdialysis, we have shown that female, but not males, display an increase in extracellular amyloid- in response to stress that persist long after the removal of the stressor. Additionally, tau increases in both males and females after stress, with females showing a dramatic 100% sustained increase, and males showing a moderate 50% increase that stays elevated for over ten hours after the removal of stress. This finding suggests that there is a different pathway at play during stress in the kinetics of amyloid- and tau. We find that -arrestin plays a role in the chaperoning of CRF-R from the cell surface in males, leading to the blunted response of amyloid- in males after stress. The mechanism behind the increase in tau seen in both males and females remains unknown, but we speculate that it is due to separate pathways, as the increase in tau in response to corticosterone injection is not seen in amyloid-. These findings suggest that sex differences in signaling in both stress pathways and hormone pathways may provide insight into the sex disparities seen in AD.

Committee Chair

John Cirrito

Committee Members

Geraldine Kress; Carla Yuede; David Holtzman; Kevin Noguchi

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

8-2-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0003-4259-8445

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