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GONADAL HORMONE REGULATION OF NEUROGENESIS AND THERAPEUTIC
IMPLICATIONS FOR NEURODEGENERATIVE DISEASES
by
Lifei Liu
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOURTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(NEUROSCIENCE)
December 2009
Copyright 2009 Lifei Liu
Object Description
| Title | Gonadal hormone regulation of neurogenesis and therapeutic implications for neurodegenerative diseases |
| Author | Liu, Lifei |
| Author email | lifeiliu@usc.edu; lifeiliu@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2009-09-21 |
| Date submitted | 2009 |
| Restricted until | Unrestricted |
| Date published | 2009-11-25 |
| Advisor (committee chair) | Brinton, Roberta |
| Advisor (committee member) |
Alkana, Ronald Neamati, Nouri |
| Abstract | Discovery of adult neurogenesis shed light on the exciting possibility that stimulation of this process can be applied as a novel regenerative strategy for CNS disease intervention. When compared to stem cell transplantation, this regenerative strategy possesses several potential advantages: first, the endogenous source of stem cells avoids immunological reactions which are not uncommon in tissue transplantation. Second, pharmacotherapy targeting the endogenous stem cell provides a potentially more costeffective therapeutic intervention than stem cell transplant. Lastly, little ethical or political concerns would apply to this strategy. While the list of intrinsic and extrinsic factors regulating adult neurogenesis is rapidly growing (Kempermann and Gage 2000; Ming and Song 2005; Pozniak and Pleasure 2006), an increasing body of literature has shed light on the involvement of gonadal hormones in this process (Gould, McEwen et al. 1997; McEwen 2002; Brinton, Thompson et al. 2008; Brinton 2009). When compared to other regulators of neurogenesis such as growth factors, gonadal hormones possess unique advantages including small molecular weight and steady penetration of blood brain barrier (Brinton 2009), making them competitive candidates as neuroregenerative therapeutics. Among the gonadal hormones, estrogens have been extensively studied for their regulatory roles in neurogenesis, and multiple laborotaries have reported its functions in promoting both neural progenitor cell proliferation and survival (Gould, McEwen et al. 1997; McEwen 2002; Brinton, Thompson et al. 2008; Brinton 2009). The effects of progesterone on neurogenesis, however, were largely undetermined. As such, I undertook a series of studies using cellular, morphological, biochemical, genomic and behavioral approaches to characterize the impact of progesterone on neurogenesis and its underlying mechanism.; In the first part of my thesis, I described the effect of progesterone in regulating neurogenesis and underlying mechanism. My experiments showed that PRA mRNA was not detected in rNPCs, whereas membrane associated PRs, Progesterone Receptor Membrane Components (PGRMC) 1 and 2 mRNA were expressed. Progesterone induced a significant increase in BrdU incorporation that was confirmed by FACS analysis, which indicated that progesterone promoted rNPC exit of G0/G1 phase at 5 hours, followed by an increase in S-phase at 6 hours and M-phase at 8 hours, respectively. Microarray analysis of cell-cycle genes and RT-PCR and Western blot validation revealed that progesterone increased expression of genes that promote mitosis while decreasing expression of genes that repress cell proliferation. Progesterone-induced proliferation was not dependent upon conversion to metabolites and was antagonized by the ERK1/2 inhibitor UO126. Progesterone-induced proliferation was isomer and steroid specific. Computational structural analysis of progesterone and its isomers indicated that the proliferative effect of progesterone is likely to be mediated by PGRMC1/2. These data demonstrate that progesterone can promote NPC proliferation with concomitant regulation in mitotic cell-cycle genes via a PGRMC/Erk pathway mechanism.; In the second part of my thesis, I extended my study to determine the effects of synthetic progetins on neurogenesis. Seven progestins were tested and experiments were carried out to determine their proliferative and neuroprotective effects in vitro. Such effects appeared to be independent of PR binding affinity. Three progestins – Nesterone, Northynodrel and LNG - exhibited both neurogenic and neuroprotective effects, and were selected for animal experiments to determine their in vivo efficacy. Results indicated that among those progestins, Nestorone was most efficacious in promoting CNS plasticity and such effect should be taken into consideration when it comes to therapeutic application.; In the last part of my thesis, I determined the neurogenic efficacy of allopregnanolone, a metabolite of progesterone, under both aging and Alzheimer’s disease burden. Previously, we demonstrated that allopregnanolone enhanced the proliferation of neural progenitor cells in vitro and reversed both neurogenic and cognitive deficits in 3-month-old triple transgenic mice of Alzheimer’s disease (3xTgAD), an age when no AD pathology is overt. In this study we analyzed the age-dependent effect of APα on neurogenic function in 6, 9 and 12-month-old 3xTgAD male mice and compared that to age-matched non-Tg ones. Results indicated that in 3xTgAD mice, APα enhanced neurogenesis in an age-dependent manner, suggesting that APα could serve as a regenerative agent and restore cognitive performance in brains affected by Alzheimer’s disease burden, potentially via promoting functional neurogenesis in the hippocampus.; The discovery that P4 and its structural analogs could promote adult rNPC proliferation highlights the potential use of those molecules as regenerative agents in adult brain. Further, the findings that progestins could differentially regulate neurogenesis demonstrated for the first time that clinical progestins could regulate CNS plasticity and such effects should be considered when using progestins for either hormone replacement therapy or contraceptive therapy. Lastly, allopregnanolone could reverse both neurogenic and cognitive deficit in a mouse model of Alzheimer’s disease, suggesting a promising strategy for promoting neurogenesis and restoration of cognitive deficit in the adult brain under both aging and neurodegenerative disease burden. |
| Keyword | Alzheimer's disease; neurogenesis; regenerative medicine; gonadal hormone; progesterone; allopregnanolone |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m2767 |
| Contributing entity | University of Southern California |
| Rights | Liu, Lifei |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Liu-3301 |
| Archival file | uscthesesreloadpub_Volume32/etd-Liu-3301.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Full text | GONADAL HORMONE REGULATION OF NEUROGENESIS AND THERAPEUTIC IMPLICATIONS FOR NEURODEGENERATIVE DISEASES by Lifei Liu A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOURTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (NEUROSCIENCE) December 2009 Copyright 2009 Lifei Liu |
