Degree Name

Master of Science (MS)

Semester of Degree Completion

2000

Thesis Director

Britto P. Nathan

Abstract

Alzheimer's disease (AD) is a neurodegerative disorder characterized by progressive memory loss and loss of cognitive function. The pathogenesis and progression of AD is poorly understood. Recently, several risk factors have been determined, however, how these risk factors function to induce AD onset has yet to be elucidated.

Apolipoprotein E genotype has been clearly demonstrated to be a risk factor for AD. The apoE2 and apoE3 isoforms appear to be protective against AD, whereas the apoE4 isoform has been implicated in the development of AD. The apoE4 allele works in a dosage-dependent fashion; that is, the greater the expression of apoE4, the earlier the onset of AD and the quicker the progression. ApoE has been clearly shown to play a central role in nerve repair and regeneration in the central nervous system (CNS) and peripheral nervous system (PNS), however, its precise functions in these repair processes remain unclear.

Recently, it has been acknowledged that significantly more females are afflicted with AD than males; this has been suggested to be due to estrogen loss at menopause. Several studies have shown that women receiving estrogen replacement therapy (ERT) have a reduced risk of developing AD, and if they do develop AD, the progression is slower and the age of onset is later. lt is thought that estrogen somehow modulates apoE levels and/or function in the CNS, however, estrogen's role in the CNS is poorly understood.

The major objective of this study was to determine the effects of estrogen on nerve regeneration in the olfactory system of mice. In order to study the effects of estrogen on nerve regeneration, mice were variectomized (OVX) and divided into four treatment groups. Estrogen or placebo pellets were implanted in the nape of the animals' necks and mice were then irrigated with either Triton (lesioned) or saline (control). Western immunoblotting techniques were then used to quantitate specific marker proteins in the olfactory bulbs. These biochemical markers shed light on regeneration events occurring within the system.

Results indicated that estrogen does indeed play a significant role in CNS repair. Lesioning was shown to recruit glial cells to the site of injury (shown by blotting for GFAP). These glial cells then up-regulate apoE in order to facilitate neuronal repair, as shown by apoE immunoblots. Estrogen treated lesioned animals showed significantly more nerve repair (shown by olfactory marker protein or OMP blots) than in the lesioned mice receiving no estrogen. Finally, blots for synaptophysin indicated that more synapses were formed in the estrogen treated lesioned group as compared to the lesioned group not receiving estrogen. In all cases, there were no significant differences between the two non-lesioned groups.

These results strongly support the notion that estrogen facilitates apoE function in nerve repair in the CNS . Further studies at the molecular level are required to understand how estrogen and apoE work in concert to facilitate nerve repair.

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