Date of Award

Fall 12-3-2024

Embargo Period

12-3-2026

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (Medical Science)

Department

Biomedical Sciences

College

College of Graduate Studies

First Advisor

Gavin Wang

Second Advisor

Robin Muise-Helmericks

Third Advisor

Adviye Ergul

Fourth Advisor

Peggi Angel

Fifth Advisor

Hainan Lang

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder linked to abnormal protein buildup in the brain and neuroinflammation. Aging is the greatest risk factor for AD, while lifestyle and environmental factors can also contribute to AD pathogenesis. Cellular senescence is a hallmark of aging that has been implicated in AD. However, the mechanisms whereby senescent cells affect brain aging and AD pathogenesis are largely unknown. This study aimed to define the role of cellular senescence in brain aging and AD progression.

We used C57/BL6 (WT) mice to evaluate senescence in healthy brains and 5xFAD mice, a common model used to study AD, to evaluate senescence in AD brains. To assess senescence during healthy brain aging and AD progression, we tested these models at various ages for evaluating senescence and senescence-mediated neuroinflammation. We further depleted senescent cells using the senolytic drug ABT-263 to examine the role of senescence in AD progression. Additionally, we used two models to examine stress-induced senescence in AD: ionizing radiation (IR) and a high-fat diet (HFD).

Our studies confirmed that AD phenotypes exacerbate age-associated cognitive decline and AD progression during aging and that these changes are associated with increased senescence. Removal of senescent cells by senolytic ABT-263 reduced AD pathogenesis. In vitro studies demonstrated that IR induces senescence and promotes the senescence-associated secretory phenotype, which includes pro-inflammatory cytokines, in microglia. A whole-brain IR in vivo model supported these findings. IR-exposed mice exhibited age-associated cognitive deficits in WT mice and AD progression in 5xFAD mice, which were associated with increased senescence-mediated neuroinflammation. Our second model, the HFD, also induced cognitive decline and AD progression, which were associated with increased senescence and other AD-associated features. Metformin mitigated HFD-induced pathological phenotypes in 5xFAD mice. JC10 and MitoSOX red assays revealed that HFD conditions promoted mitochondrial dysfunction and oxidative stress in BV-2 microglia cells, and metformin prevented these HFD-induced changes.

We conclude that age-associated and stress-induced senescence promotes brain aging and AD progression. Additionally, our findings demonstrated that metformin mitigated HFD-induced senescence and AD progression and may do so by preventing mitochondrial dysfunction and oxidative stress, which are major drivers of senescence.

Rights

Copyright is held by the author. All rights reserved.

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Available for download on Thursday, December 03, 2026

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