Student Theses and Dissertations

Date of Award

2007

Document Type

Thesis

RU Laboratory

McEwen Laboratory

Keywords

neurodegenerative diseases, microglia, microglia activation, steroid hormones, corticosterone, E2

Abstract

The conditions defining whether microglial activation is detrimental or beneficial to neuronal survival are still poorly understood. Better understanding of the factors regulating microglia activation may lead to improved therapies for neurodegenerative diseases. Clinical and animal studies point to the neuroprotective and anti-inflammatory effects of steroid hormones. However, our comprehension of the cellular targets and mechanisms of action of these hormones in the CNS is still unresolved. In view of these limitations, the main question addressed in this dissertation was the role that microglia play in the anti-inflammatory effects of steroid hormones in the brain, with particular emphasis on the neuroprotective hormone 17β-estradiol (E2), and the anti-inflammatory steroid, corticosterone. To address this problem, microglia culture models were established using a microglia cell line and primary cultures from transgenic mice that facilitate the identification of microglia by EGFP expression. Collaborative studies were also done in mice in vivo. The expression of steroid hormone receptors was studied as well as their function. This dissertation shows that microglia cells are not direct targets of estrogen actions, but respond profoundly to glucocorticoids, which exert anti-inflammatory effects on the production of cytokines like TNFα, IL-6 and NO. Steroid hormones can be produced within the brain. In this dissertation, microglia cells are shown to participate in the metabolism of steroids through expression of steroidconverting enzymes. Expression of 11βHSD1 in microglia mediated an autocrine re-activation of glucocorticoids, whereas, expression of enzymes like 17βHSD1 and 5αR catalyzed the conversion of active androgens and estrogens from steroid hormone precursors AD and DHEA. These microglia-derived hormones had estrogenic effects on neuronal cells, as described in the last section of this dissertation where the characterization and responsiveness of a neural progenitor cell line are presented. In summary, microglia cells are highly susceptible to the action of glucocorticoids, but not estrogens. This specificity is dictated by the abundant expression of glucocorticoid receptors, and a minimal expression of estrogen receptors. A novel role of microglia is also presented. Microglia express steroid-metabolizing enzymes, which mediate the autocrine reactivation of glucocorticoids, or the production of active androgens and estrogens from steroid hormone precursors.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Permanent URL

http://hdl.handle.net/10209/123

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