Date of Award
2025
Degree Type
Dissertation
Degree Name
Doctor of Philosophy in Interdisciplinary Neuroscience
Department
Cell & Molecular Biology
First Advisor
Claudia Fallini
Abstract
Stroke and Alzheimer’s disease and related dementias (ADRD) represent two of the leading causes of neurological disability worldwide, and their prevalence is expected to rise as the global population ages. Although stroke is traditionally viewed as an acute vascular event, a growing body of evidence suggests that transient ischemic injury can trigger lasting cellular disturbances that increase neuronal vulnerability to later neurodegeneration. Understanding how ischemic stress alters neuronal structure and function, and how these changes may overlap with pathways implicated in ADRD, is an emerging focus for stroke and neurodegenerative researchers. This dissertation addresses these questions through an integrated combination of human iPSC-derived neuronal models, and a preliminary in vivo stroke model.
The first chapter provides a comprehensive review of the clinical, epidemiological, and mechanistic links between stroke and ADRD, emphasizing shared cellular pathologies such as excitotoxicity, oxidative stress, impaired proteostasis, and chronic neuroinflammation. The second chapter examines early on survival of transient oxygen-glucose deprivation (OGD) in iPSC-derived human cortical neurons and how a panel of phytocannabinoids may be able to attenuate the neuronal loss after reperfusion. The third chapter investigates how OGD in iPSC-derived neurons triggers cytoskeletal changes, disrupting nuclear-cytoskeletal coupling, and destabilizing key nuclear structures. Downstream consequences of this include depletion of the RNA-binding protein TDP-43 depletion, activation of the cyclic GMP-AMP synthase- Stimulator of Interferon Genes (cGAS-STING) activation and overall decrease in survival. Furthermore, features of molecular neurodegeneration following ischemic stress and are exacerbated by repeated injury. Finally, the fourth chapter aims to validate phenotypes seen in chapter three in an animal model of photothrombotic stroke model. This chapter presents preliminary data that shows early peri-infarct alterations in nuclear morphology and LINC complex components that parallel injury signatures observed in vitro.
Overall, this dissertation identifies cytoskeletal remodeling and nuclear instability as early, convergent injury pathways that may prime post-stroke neurons for accelerated neurodegeneration. These findings help elucidate mechanisms that may underly stroke driven degenerative cascades co-implicated in ADRD, highlighting nuclear structural integrity and the cytoskeleton as a potential target for future therapeutic intervention.
Recommended Citation
Potts, Emily, "ISCHEMIA-INDUCED CYTOSKELETAL AND NUCLEAR DISRUPTIONS DRIVE NEURONAL DEATH AND DYSFUNCTION: INSIGHTS INTO THE CONNECTION BETWEEN STROKE AND DEMENTIA FROM IN VITRO AND IN VIVO MODELS OF STROKE" (2025). Open Access Dissertations. Paper 4530.
https://digitalcommons.uri.edu/oa_diss/4530