Graduate Program

Biological Sciences

Degree Name

Master of Science (MS)

Semester of Degree Completion

2012

Thesis Director

Britto P. Nathan

Thesis Committee Member

Zhiwei Liu

Thesis Committee Member

Gary A. Bulla

Abstract

Apolipoprotein E (apoE) is well studied for its role in cholesterol transportation and metabolizing lipoproteins. ApoE is found in the olfactory system especially in the olfactory nerve and glomeruli of the olfactory bulb. Studies from our laboratory indicate that apoE is a required component for timely regeneration and olfactory receptor neuron maturation. The mechanism for which apoE contributes to neuron function and developing late onset Alzheimer's disease is still being studied. A mutant form of apoE (apoE 4) is believed to be a prominent genetic risk factor for this neurodegenerative disease. Over sixty percent of Alzheimer's disease patients in the United Sates are women. This revelation has concentrated more focus on the loss of estrogen as a potential risk factor. To better understand how apoE and estrogen may contribute to Alzheimer's disease, this study utilizes apoE knockout mice and estradiol treatment.

Using the olfactory system as a model, the right olfactory bulb was removed from all treatments of wild type (WT) and apoE knockout (KO) mice. Retrograde olfactory receptor neuron death and regeneration was observed between males and females of both genotypes in the olfactory epithelium. The results show massive olfactory receptor neuron death within days of olfactory bulb ablation in male mice compared to their female counter part. When estrogen was given at above the physiological dose, the duration of neuroprotection increased. However, when no estrogen was present olfactory receptor neurons died faster. Overall, mice treated with estrogen exhibited a more rapid rate of regeneration regardless of the presence of apoE.

Animals without apoE illustrated similar results to those with apoE but the average data values were slightly lower for apoE knockout mice than WTmice, illustrating that apoE is required for proper olfactory epithelium maintenance. These results were fairly consistent 4 throughout the data; however data for estradiol treated animals varied among genotypes. To measure the rate of olfactory receptor neuron death olfactory epithelium thickness was measured at 3, 7 and 21 days following olfactory bulbectomy. To observe the rate of death of mature olfactory receptor neurons olfactory marker protein (OMP) immunohistochemistry was performed. To gauge the rate of globose basal (stem) cell division bromodeoxyuridine (BrdU) immunohistochemistry was performed. By removing the olfactory bulb, the target for olfactory receptor neuron which served as the signal transduction, the olfactory epithelium fails to return to its original thickness suggesting olfactory receptor neuron maturity is dependent on proper target connectivity.

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