Author ORCID Identifier

0009-0007-7403-3138

Date of Graduation

5-2026

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Louise McCullough, MD PhD

Committee Member

Akihiko Urayama, PhD

Committee Member

Juneyoung Lee, PhD

Committee Member

Qingchun Tong, PhD

Committee Member

Nicholas Justice, PhD

Committee Member

Changqing Ju, PhD

Abstract

Background: Cerebral amyloid angiopathy (CAA) is a form of vascular dementia characterized by accumulation of amyloid-beta (Aβ) in the walls of cerebral and leptomeningeal blood vessels, leading to vascular dysfunction, neuroinflammation, and cognitive impairments. Impaired clearance of Aβ, especially by peripheral organs, is hypothesized to be a major driver of amyloid-related pathologies. The liver is the primary peripheral organ involved in Aβ clearance and hepatic inflammation or dysfunction is associated with exacerbated CAA pathology and progression. Prior work from preclinical models has suggested sexual dimorphism in hepatic inflammation and lipid regulation, but the exact progression of these alterations and their impact on cerebral pathology remains unknown. Thus, the objective of this work is to better understand liver dysfunction and inflammation, and the progression of these changes across various stages of pathology using a mouse model of CAA. A secondary objective is to compare in vivo findings with hepatic pathology in CAA patients to establish the translational relevance and validity of the liver-brain axis in CAA.

Hypothesis: I hypothesized that TgSwDI mice will exhibit progressive, sex-dimorphic hepatic dysfunction including increased inflammation, steatosis, and fibrosis. In addition, impairments in hepatic function will be associated with greater cerebral Aβ40 burden.

Methods: To address these questions, I first characterized inflammatory and pathological hepatic phenotypes across multiple ages in male and female TgSwDI mice. Age-matched wild-type (WT) controls were included to distinguish the specific effects of CAA pathology from natural age-related hepatic inflammation and dysfunction. I then examined the relationship between hepatic alterations and cerebral Aβ burden. Finally, to assess translational relevance, I evaluated post-mortem liver tissues from patients with CAA to determine whether similar pathological features could be identified in humans.

Results: Using a transgenic mouse model at several disease stages, I demonstrated novel alterations in hepatic lipid regulation and inflammation. Male CAA mice showed an elevation in serum levels of hepatic enzymes. Males and females showed very distinct trends in hepatic lipid accumulation across all tested phases. Hepatic inflammation was significantly increased in females at advanced stages of disease, which was shown to coincide with exacerbated cerebral pathology. Several of the effects observed in the mouse model were mirrored in human samples, including elevated liver function enzymes specifically in men with CAA and greater hepatic inflammation in women with CAA.

Summary: This study represents the first systematic characterization of hepatic function, inflammation, and lipid regulation in a mouse model of CAA. It is also the first study to examine hepatic pathology in human CAA patients. Overall, this study demonstrates novel sex-specific alterations in hepatic function that may have profound consequences on the development or progression of cognitive impairments and dementia. Specifically, males display altered liver chemistries while females display exacerbated hepatic inflammation. Furthermore, this study establishes that CAA is not confined to the brain, and suggests peripheral organ health as a novel driver or modifier of cerebral pathology, thereby opening a new axis of investigation in an understudied disease.

Keywords

cerebral amyloid angiopathy, liver, amyloid-beta, vascular dementia

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Available for download on Friday, April 30, 2027

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