Degree Name

Master of Science (MS)

Semester of Degree Completion

2002

Thesis Director

Britto P. Nathan

Abstract

Estrogen replacement therapy appears to delay the onset of Alzheimer's disease (AD). The mechanism whereby estrogen prevents the pathogenesis of AD is unknown. In the present study, I examined the effects of 17-β-estradiol (E2) on neurite outgrowth from adult mice cortical neurons (AMC) in culture. I found that E2 increases apoE secretion and neurite outgrowth in AMC neurons from wild type mice in a dose dependent fashion. The neurite outgrowth promoting effect of E2 was not observed in AMC neurons derived from age-, sex-, and stain-matched apoE deficient/apoE gene knockout (apoE KO) mice. Furthermore, E2 has isoform specific effects on neurite outgrowth in the presence of purified recombinant human apoE. The presence of human apoE2 or apoE3 greatly augmented E2 effects on promoting neurite outgrowth, whereas the presence of apoE4 had no significant effect. Consistent with these findings, E2 had differential effects on neurite outgrowth from AMC neurons derived from transgenic mice expressing human apoE isoforms. Incubation of AMC neurons from apoE3 transgenic mice with E2 significantly increased neurite outgrowth, whereas incubation of AMC neurons from apoE4 transgenic mice with E2 had no significant effect. In summary, my data suggest that apoE isoforms play a critical role in mediating the neurite outgrowth promoting effect of E2.

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