Author ORCID Identifier
Document Type
Dissertation
Date of Award
2026
Degree Name
Doctor of Philosophy (PhD)
Department
Basic Biomedical Science
First Advisor
Samuel Sathyanesan
Abstract
Alzheimer’s disease (AD) is a prominent neurodegenerative disease characterized by a decline in cognitive functioning. While current FDA-approved therapeutics exist, they fall short in creating significant and long-lasting improvements to cognition. A newer approach using neurotrophic factors has shown promising effects on improving cognition in clinical trials. Neurotrophic factors are secreted proteins that have multimodal effects in the brain, including supporting cell survival and functioning. Two neurotrophic factors of interest are carbamoylated erythropoietin (CEPO) and insulin-like growth factor-1 (IGF-1), and the goal of this study was to understand the synergistic and neuroprotective effects of CEPO and IGF-1 in AD. We first showed that CEPO and IGF-1 have synergistic effects on gene and receptor expression in vitro but find that this effect is not mediated by synergistic effects on kinase phosphorylation. To better define phosphorylation changes downstream of neurotrophic factors, we examined the phosphoproteome of IGF-1 in neuronally-differentiated cells. This analysis identified increased synaptogenesis and RhoGTPase cycle signaling, highlighting that IGF-1 has broad roles in learning and memory and at the synapse. To define the effects of CEPO and IGF-1 in AD, we performed a long-term neuroprotective study in 5xFAD mice, an AD genetic mouse model, and looked at the effects on behavior and protein expression in the brain. Both CEPO and IGF-1 were able to protect against behavioral deficits in the male, but not the female, 5xFAD mice when given individually. When combined, this protective effect on behavior was absent. Further analysis found that simultaneous signaling pathway activation is crucial for eliciting synergistic effects, which was lacking here. When examining protein expression, CEPO and IGF-1 were able to reduce phosphorylated tau (p-tau) expression in the brains of the 5xFAD mice in both males and females, but neither neurotrophic factor influenced amyloid-β (Aβ) expression. The accumulation of p-tau and Aβ are hallmarks of AD, but p-tau accumulation has shown stronger links to cognitive decline, highlighting that reduced p-tau could be a mechanism through which CEPO and IGF-1 are improving cognition. These data provide insight into the pro-cognitive mechanism of neurotrophic factors and begin to define neurotrophic factor synergism in vivo.
Subject Categories
Biology | Neuroscience and Neurobiology
Keywords
Alzheimer's disease CEPO IGF-1 Neuroprotective Neurotrophic factors Synergism
Number of Pages
175
Publisher
University of South Dakota
Recommended Citation
Jean Rothschadl, Morgan, "The neuroprotective and synergistic effects of carbamoylated erythropoietin and insulin-like growth factor-1 in Alzheimer's disease" (2026). Dissertations and Theses. 393.
https://red.library.usd.edu/diss-thesis/393