Date of Award
Fall 10-10-2024
Embargo Period
10-10-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Medicine
College
College of Graduate Studies
First Advisor
Federica del Monte
Abstract
Heart failure (HF) and Alzheimer’s Disease (AD) are two leading causes of death in the United States. Conventionally viewed as independent conditions, HF/AD coexist in ~30% of patients and are mechanistically linked by shared genetic and biochemical characteristics. The del Monte lab has established the concept of the heart-brain axis through human samples and murine models, providing a framework for this dissertation which focuses on the interplay between genetics and the environment in shaping the heterogeneity of disease phenotypes.
1) Loss of function mutations in presenilin (PSEN1/2) genes represent overlapping genetic signatures in AD/HF. Presenilins form the g-secretase catalytic subunit but also serve to regulate Ca2+, critical for neuron and cardiomyocyte function. Effects of PSEN2 loss concurrently in the heart and brain is unknown. Leveraging a mouse model of PSEN2 deletion (PS2KO), we found PS2KO mice have increased anxiety and diastolic dysfunction in-vivo and in vitro. Our data demonstrates PSEN2 loss induced Ca2+ handling defects, contributing to the development of coexistent myocardial and cognitive decline.
2) Familial HF, like AD, accounts for ~5% of cases, whereas majority are sporadic with/without genetic mutation. As such, investigating interactions between genetics and exposures to environmental modifiers is crucial to understanding the factors that influence prevalence and progression of disease. In AD and HF, environmental modifiers may influence organ(s) dysfunction through accelerating the misfolding of proteins. Air particulate matter (PM) has been independently linked to adverse cognitive and cardiovascular effects. However, its pathological effect concurrently on both organs and by which mechanism(s) is unknown. We found that exposure to PM in wildtype and AD model mice (APPswe/PSEN1DE9) affects cognition and cardiac function through amyloid-beta pathology, oxidative stress, and lung microbial dysbiosis. These data suggest that PM works independently, and in synergy with AD genetics, to influence disease in the heart and brain.
We demonstrated that AD pathology and functional deficits extend beyond the brain to affect the heart due to both genetics alone and when interplayed with environmental modification. Our data provides an explanation for the heterogeneity of HF/AD phenotypes, and suggests that early intervention is crucial to modify disease progression in both organs.
Recommended Citation
Butler, Helen, "The Heart-Brain Axis: Exploring Shared Genetic Signatures and Environmental Modifiers on Heart Failure and Alzheimer’s Disease Pathology" (2024). MUSC Theses and Dissertations. 961.
https://medica-musc.researchcommons.org/theses/961
Rights
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