| Dissertation |
Thesis (Ph.D.) --NUI, 2010 at Department of Anatomy, University College Cork. |
| Summary |
Neurogenesis occurs in the hippocampus of both the developing and adult brain due to the presence of multipotent stem cells and restricted precursor cells at different stages of differentiation. These cells can be isolated from the brain, cultured and manipulated in vitro as ‘neurosphere' cultures. Given appropriate signals, cells from these cultures can differentiate into neurons, astrocytes or oligodendrocytes. Neurogenesis is thought to be impaired in certain neurodegenerative disorders such as Alzheimer's disease. In the Alzheimer's diseased brain, large numbers of activated microglia have a deleterious effect on newly formed neurons through the action of the pro-inflammatory cytokines, Interleukin 1β (IL-1β) and Tumour necrosis factor α (TNFα). An initial investigation was carried out to characterise the cellular composition of embryonic hippocampal neurosphere cultures. This set a baseline for the next series of investigations which was to examine the effects of TNFα and IL-1β-treatment during proliferation or differentiation on the lineage fate of cells in these cultures of embryonic hippocampal neurospheres. Treatment with IL-1β or TNFα during differentiation was found to have a detrimental effect on neuronal development by inhibiting the differentiation of precursor cells to a neuronal phenotype, and by promoting their differentiation to an astroglial phenotype. On the other hand, treatment with IL-1β or TNFα during proliferation had no effect on neuronal development and decreased astrocytes but lead to an increase in proliferating precursor cells. The final phase was to investigate the effect of the IL-1 receptor antagonist (IL-1ra) on the previously observed IL-1β-induced effects. The effects of IL-1β in the presence and absence of IL-1ra on the differentiation of neuronal and astroglial cultures in embryonic hippocampal neurospheres was assessed. This investigation was followed with a similar study in the adult hippocampus in vivo. IL-1ra antagonised the effects of IL-1β in vitro reversing the detrimental effects IL-1β had on neurons. IL-1β or IL-1ra intracerebroventricular treatment in vivo, however, had no significant effect on the lineage fate of newly-born neurons or proliferating cells in the dentate gyrus. By studying the effects of cytokines on the proliferation of embryonic hippocampal neural stem cells, a model for the effects of cytokines on these cells can be extrapolated. In this study, it was found that cytokines have a negative effect on the proliferation of hippocampal neural stem cells in vitro. This implies that the presence of increased levels of cytokines in diseases such as Alzheimer's disease may have a detrimental effect on the ability of the hippocampal stem cells to proliferate in vivo and therefore reduce their capacity to replace cells that are lost during the natural progression of the disease. Exploring the intrinsic mechanisms, environmental cues, and inflammatory signals that control neurogenesis in the brain can help identify new drug targets which may be manipulated to prevent inflammation induced impairment of neurogenesis and the death of newly-born neurons. This study contributes to the knowledge required for the development of cell-based regenerative therapies for neuro-inflammatory disorders. |
| Add Form |
Also available on Cd-Rom. |
| Subject |
Anatomy.
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| Collection |
Theses Ph.D.
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Theses Anatomy Department
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| Description |
2 v. : ill. ; 30 cm. + 1 cd-rom 4 3/4 in. |
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