Steroids and Lipoproteins in the CNS

Apolipoprotein E production in the adult rodent brain is also influenced by estrogen. Again, this effect is dependent upon genotype and varies between brain regions. Of four mouse strains studied,22 brain apoE mRNA was affected by estrogen in only the C3H mouse strain, which showed increased brain apoE mRNA levels in response to 17p-estradiol (E2) for 5 days. Changes in apoE mRNA are also apparent in various brain regions of the F344 rat during the normal estrous cycle. In the arcuate nucleus, synaptic remodeling occurs during the normal rat estrous cycle, with synapse number decreasing on the afternoon of proestrus when estrogen levels are highest (Fig. 3.1). This decrease occurs prior to the luteinizing hormone (LH) surge which cases ovulation.23 This decrease is transient, and caused by estrogen.24 We found that during this estrogen-induced synaptic remodeling, apoE mRNA levels are also transiently increased (Fig. 3.2A).

Likewise, the hippocampal CA1 also undergoes transient estrogen-induced synaptic remodeling.25 In the stratium radiatum of the CA1 both dendritic spine and synaptic density are increased on proestrus, and apoE mRNA levels also appear to be under estrogenic control in this region. On proestrus, when circulating estrogen levels are highest, apoE mRNA levels were found to be 30 to 70% higher than on other cycle days.26 In the same study, however, apoE mRNA levels were highest on diestrus in the CA3, when circulating estrogen levels are considerably lower. These results are not surprising as specialized subpopulations of astrocytes occur with different frequencies in the CA1 and CA3.27 This would suggest differential regulation of apoE mRNA levels in different astrocyte subpopulations/different brain regions. These findings, however, do not constitute direct evidence that estrogen influences apoE mRNA in vivo, as levels of several other hormones also differ between cycle days (Fig. 3.1).28

Estrogenic control of apoE mRNA is directly shown in vitro. In mixed glial cultures (65-75% astrocytes, 15-20% microglia, 10-15% oligodendrocytes; originated from cerebral cortex from 1-5 day old rat pups), the levels of apoE mRNA are increased 2-fold by the addition of 17p-estradiol at a concentration of 0.1nM (approximately blood levels at late proestrus or pregnancy). This apoE induction occurs in both astrocytes and microglia. However, no induction is caused by corticosterone or dihydrotestosterone (Fig. 3.3). This upregulation is dependent upon cell-cell interactions, as neither astrocytes or microglia respond to estrogen with increased apoE mRNA when grown in monotypic culture.26 Cell-cell contact is also necessary for this increase,29 as separation of astrocytes and microglia with a 0.45 |im pore-size filter removed the estrogen effect.

Astrocytic apoJ mRNA is also under estrogen control in vitro: We demonstrated 2-fold increase of apoJ mRNA in both monotypic astrocyte and mixed glial cultures (Rozovsky et al, unpublished data).

Fig. 3.1. Concentration of progesterone, prolactin, estradiol, LH, and FSH in peripheral plasma obtained at 2 h intervals throughout the 4 d rat estrous cycle. Each point represents mean (± SE) of 5-6 rats. Black bars represent dark interval (1800-0600); numbers below represent time of day. Redrawn from ref. 28.

Fig. 3.1. Concentration of progesterone, prolactin, estradiol, LH, and FSH in peripheral plasma obtained at 2 h intervals throughout the 4 d rat estrous cycle. Each point represents mean (± SE) of 5-6 rats. Black bars represent dark interval (1800-0600); numbers below represent time of day. Redrawn from ref. 28.

Fig. 3.2. Apolopoprotein E mRNA levels are increased with estrogen in vivo. (A) In the rat arcuate nucleus, which undergoes transient synaptic remodeling during the estrous cycle, apoE mRNA levels peak on proestrus, when estrogen levels are highest.26 (B) In EC-lesioned mice, apoE mRNA levels at the wound site and in the deafferented dentate gyrus followed estrogen-dependent trends at 14 days post lesion which were not significant. Redrawn from ref. 26.

Fig. 3.2. Apolopoprotein E mRNA levels are increased with estrogen in vivo. (A) In the rat arcuate nucleus, which undergoes transient synaptic remodeling during the estrous cycle, apoE mRNA levels peak on proestrus, when estrogen levels are highest.26 (B) In EC-lesioned mice, apoE mRNA levels at the wound site and in the deafferented dentate gyrus followed estrogen-dependent trends at 14 days post lesion which were not significant. Redrawn from ref. 26.

In vivo, gonadal steroids also appear to have an effect on apoJ mRNA, and this effect is again dependent upon the species. Castration of male rats for 3 weeks increases the level of apoJ mRNA in both the normal and deafferented hippocampus.30

In a different study we manipulated estrogen levels in mice through OVX and estrogen replacement, after which we lesioned the entorhinal cortex to examine reactive synaptogenesis and apolipoprotein production.31 This study was carried out on both wild type mice (WT) and transgenics lacking the apoE gene (apoE KO). While OVX did not decrease apoJ mRNA production, the OVXed mice with E2 replacement showed a 1.7-fold increase in apoJ mRNA

Fig. 3.3. Glial cells in vitro respond to E2 17ß-estradiol treatment with increased apoE mRNA. (A) Dose response curve: Mixed glial cells show a 2-fold increase in apoE mRNA at 0.1 nM, approximating high proestrous levels. (B) Secreted protein shows a small, nonsignificant increase, while cellular protein shows a highly significant 4-fold increase (p<0.001). This increase in cellular protein may signify an increase in uptake, which could be mediated by either increased receptor expression or affinity. (C) Analysis by in situ hybridization demonstrates that both astrocytes and microglia respond to estradiol, but not to other steroids. Redrawn from ref. 26.

Fig. 3.3. Glial cells in vitro respond to E2 17ß-estradiol treatment with increased apoE mRNA. (A) Dose response curve: Mixed glial cells show a 2-fold increase in apoE mRNA at 0.1 nM, approximating high proestrous levels. (B) Secreted protein shows a small, nonsignificant increase, while cellular protein shows a highly significant 4-fold increase (p<0.001). This increase in cellular protein may signify an increase in uptake, which could be mediated by either increased receptor expression or affinity. (C) Analysis by in situ hybridization demonstrates that both astrocytes and microglia respond to estradiol, but not to other steroids. Redrawn from ref. 26.

levels in the lesioned entorhinal cortex (Fig. 3.4). Thus there may be an interaction between estrogen and progesterone (or some other ovarian hormone), such that E2 only causes an apoJ increase in the absence of progesterone. Apolopoprotein E-KO mice also showed a complex hormonal effect, with apoJ mRNA increasing in the deafferented dentate gyrus after OVX, with or without E2 replacement (Fig. 3.4B).

Experiments with rats also suggest some form of interactions between apoJ mRNA and ovarian steroids other than estrogen. After entorhinal cortex lesioning (ECL), rats which were also OVXed have 20% higher apoJ mRNA levels in the deafferented dentate gyrus (p<0.025) over intact controls (Stone and Rozovsky, unpublished data). Estrogen replacement

Fig. 3.4. Both WT and apoE-KO mice show a possible progesterone effect on apoJ mRNA levels. (A) In WT mice, OVXed mice with E2 replacement show increased levels of apoJ mRNA in the entorhinal cortex after EC-lesioning, suggesting estrogen/progesterone interactions. (B) In apoE KO mice, removal of the ovaries increases apoJ mRNA levels in the deafferented dentate gyrus with or without E2 replacement, suggesting a progesterone effect. These results also suggest some form of coordination in apoE and apoJ production, as the apoE-null state changes the apoJ response to ovarian hormones. Lesioning/OVX experiments with progesterone replacement will be necessary to elucidate the interaction of estrogen and progesterone on cholesterol transport. Redrawn from ref. 31.

Fig. 3.4. Both WT and apoE-KO mice show a possible progesterone effect on apoJ mRNA levels. (A) In WT mice, OVXed mice with E2 replacement show increased levels of apoJ mRNA in the entorhinal cortex after EC-lesioning, suggesting estrogen/progesterone interactions. (B) In apoE KO mice, removal of the ovaries increases apoJ mRNA levels in the deafferented dentate gyrus with or without E2 replacement, suggesting a progesterone effect. These results also suggest some form of coordination in apoE and apoJ production, as the apoE-null state changes the apoJ response to ovarian hormones. Lesioning/OVX experiments with progesterone replacement will be necessary to elucidate the interaction of estrogen and progesterone on cholesterol transport. Redrawn from ref. 31.

did not reverse this effect, implicating progesterone or some other ovarian hormone as the cause of this increase. Progesterone was not directly manipulated in these studies.

Was this article helpful?

0 0
Hair Loss Prevention

Hair Loss Prevention

The best start to preventing hair loss is understanding the basics of hair what it is, how it grows, what system malfunctions can cause it to stop growing. And this ebook will cover the bases for you. Note that the contents here are not presented from a medical practitioner, and that any and all dietary and medical planning should be made under the guidance of your own medical and health practitioners. This content only presents overviews of hair loss prevention research for educational purposes and does not replace medical advice from a professional physician.

Get My Free Ebook


Post a comment