Interaction Of Apoe With Estrogen In The Olfactory System During Nerve Maintenance And Recovery

Abstract

Estrogen replacement profoundly aids in nerve regeneration after injury in adult mammalian models. Estrogen replacement also protects against olfactory dysfunction in mammals. The mechanism underly1ng estrogen's neuroprotective effects remains ambiguous. My goal is to investigate and better clarify if apolipoprotein E (apoE ), a lipid transporting protein, is a critical intermediary to estrogen's effects on nerve maintenance and regeneration.

My hypothesis is that apoE is a mediator of estrogen's beneficial effects. This hypothesis is based on the following observations from previous studies. First, olfactory nerve regeneration was delayed in apoE-gene knockout (KO) mice as compared to wild type (WT) mice. Second, 17B-estradiol replacement in ovariectomized (0VX) mice resulted in a significant increase in levels of apoE and its receptor, LRP, in the olfactory bulb. Third, estradiol treatment increased both apoE and neurite outgrowth in cortical and olfactory neuronal cultures. Fourth, estradiol treatment had no effect on neurite outgrowth in cultures derived from apoE KO mice. This thesis study focuses on in vivo studies in the olfactory system.

I evaluated estrogen and apoE in the olfactory nervous system during normal nerve maintenance and during nerve repair post injury over a period of 56 days. WT and KO mice were treated with either a placebo or 17B-estradiol pellet. The olfactory epithelium (OE) and the olfactory bulb (OB) were examined by means of cresyl violet staining and immunohistochemistry. Staining performed in the OE investigated thickness, apoE, cell division, immature olfactory receptor neurons (0RNs), and mature 0RNs. Staining in the OB investigated 0MP and SYN immunoreactivity and astrocytes.

My results indicated that estrogen and apoE are critical in supporting olfactory nerve maintenance and regeneration in mice. Estrogen increased apoE which turn facilitated maturation of olfactory neurons in the olfactory system over time. Also, nerve repair was faster and more efficient the presence of estrogen. Estrogen increased cell division early in the repair process via an apoE requiring mechanism. Additionally, estrogen repaired the olfactory nerve beyond normal maturation in WT mice. In contrast to WT mice, KO mice nerve repair was slower and incomplete. Furthermore, estrogen had no effect on the rate of olfactory nerve regeneration in KO mice.

Date of Award	2009
Original language	American English
Awarding Institution	Eastern Illinois University
Supervisor	Britto P. Nathan (Supervisor)