The Liver-Brain Axis in Cerebral Amyloid Angiopathy

Shivi Garg (Advisor: Louise McCullough, MD, PhD)

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.

Hypothesis: CAA is expected to be associated with age- and sex-dependent alterations in hepatic inflammation and metabolic function. These differences are expected to be more pronounced in younger and middle-aged mice due to contributions from gonadal hormones.

Methods: To address these questions, I first characterized inflammatory and pathological hepatic phenotypes across multiple ages in male and female TgSwDI mice. 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 demonstrate novel alterations in hepatic lipid regulation and inflammation. Males and females show very distinct trends in hepatic lipid accumulation across all tested phases. Hepatic inflammation is significantly increased in females at advanced stages of disease, which is shown to coincide with exacerbated cerebral pathology. A similar pattern was also observed in post-mortem tissues from CAA patients, with females exhibiting heightened hepatic inflammation compared to both male patients and healthy controls. Lastly, positive evidence for Aβ uptake in human liver further validates our in vivo findings, and enhances the translational value of this study.

Summary: 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. Furthermore, it highlights the need for deeper investigation into peripheral modifiers of cerebral disorders to enhance our understanding of, and eventually improve outcomes for the disproportionate disease burden faced by women.

Advisory Committee:

• Louise McCullough, MD, PhD, Chair
• Changqing Ju, PhD
• Nicholas Justice, PhD
• Juneyoung Lee, PhD
• Qingchun Tong, PhD