Date of Award

2022

Document Type

Honors Thesis (Open Access)

Department

Colby College. Biology Dept.

Advisor(s)

Melissa Glenn

Second Advisor

Tariq Ahmad

Third Advisor

Lynn Hannum

Abstract

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that affects over 5 million individuals in the United States alone. While AD is primarily thought of as a disease that destroys neural networks required for memory recall and formation, AD also cause impairment in emotional regulation, cognitive flexibility, and executive function pathways. The cause of AD is unknown; however, the allele ApoE4 has been identified as a risk factor for the onset of AD. ApoE4 provides a valuable opportunity to study AD through animal models. This thesis utilized a human ApoE4 transgenic rat model (hApoE4) to investigate the biological and behavioral consequences of this AD risk allele. Cellular stress, hippocampal regulation, and behavioral tests evaluating rat cognitive function were analyzed. Cellular stress was assessed through the quantification of a novel biomarker, Growth Differentiation Factor-15 (GDF-15). Hippocampal regulation was examined in the context of neurogenesis occurrence (Doublecortin) and GABAergic neuron prevalence (Parvalbumin). It was revealed that GDF-15 serum concentrations significantly increase with age in wildtype and ApoE4 male rats, but not in ApoE4 female rats. In addition, ApoE4 males demonstrated a trend towards a reduction in PVB+ interneurons. These findings were correlated with behavioral testing data. Correlational analysis suggested the investigated biomarkers were associated with the cognitive function of hApoE4 rats, as evaluated through behavioral tests. Of most significance, this paper provides evidence suggesting the ApoE4 allele functions in a sex-dependent manner in rats, and directly alters GDF-15 levels in a potentially neurodestructive manor in female ApoE4 rats.

Keywords

Alzheimer’s Disease, Differentiation Factor-15 (GDF-15), Parvalbumin (PVB), Transgenic rat model hApoE4, Neuroscience

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