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Neural stem cell recruitment in prion disease

Prodromidou, K; (2008) Neural stem cell recruitment in prion disease. Doctoral thesis , UCL (University College London). Green open access

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Neurogenesis can be induced by several physiological and pathological conditions, such as environmental enrichment, stroke, epilepsy or inflammatory demyelination. The aim of this project was to investigate the possible effect of prion disease on neurogenesis, i.e. proliferation and differentiation of neural stem cells with a particular focus on the hippocampus and the neurogenic area of the dentate gyrus. We studied stem cell recruitment in non-infected and prion infected wild type mice. In addition, we examined transgenic mice which express prion protein at 3 times wt level (tg37), show profound hippocampal degeneration upon scrapie infection and that can be rescued by Cre-mediated inactivation of the Prnp gene in neurons. Stem cell proliferation and differentiation was analysed by immunostaining of vibratome sections. To study stem cell proliferation, scrapie-infected and control mice received one intraperitoneal injection of BrdU (50 pg/g body weight) 30 minutes before culling. BrdU gets incorporated into proliferating cells. To study differentiation of labelled cells, animals were culled at different time points after BrdU injection (e.g. 7 and 8 days). BrdU-labelled cells were further characterised by the expression of astroglial (GFAP) and early neuronal (p-tubulin) markers using double labelling immuno-fluorescence. Also, we identified proliferating microglial cells using the marker Iba-1. Neuropathology of prion infected animals was assessed by immunostaining of paraffin-embedded brain sections. Cellular morphology was examined by haematoxylin and eosin staining. Astrogliosis and microglia activation was analyzed by immunostainings for the astroglial marker GFAP and the microglial marker Iba-1 respectively. Finally, PrPSc accumulation was verified by immunostaining with the PrP-specific antibody ICSM35. Late-stage scrapie increased cell proliferation in the hippocampus but not the dentate gyrus of wild type mice while it profoundly increased cell proliferation throughout the area of the hippocampus of tg37 transgenic mice. BrdU-labelled proliferating cells in the dentate gyrus of wt mice acquired a neuronal phenotype within 8 days, thus confirming that BrdU labelling identifies proliferating progenitor cells, and further that the cell proliferation we estimated in the dentate gyrus partly reflects proliferation of stem cells. Proliferating cells in the dentate gyrus of prion- infected tg37 mice were identified as astrocytes and microglial cells. Also there was a significant increase in BrdU-labelled cells expressing P-tubulin. Inactivation of PrP expression in neuronal cells during scrapie incubation, significantly decreased cell proliferation in the hippocampus. This decrease in part corresponded to a reduction in the number of proliferating astrocytes and microglial cells in the dentate gyrus. However, the number of proliferating cells acquiring a neuronal phenotype (P-tubulin positive) was unaffected by PrP depletion (and the subsequent reversal of clinical prion disease) at least at an early time point following PrP depletion. Depletion of neuronal PrP also led to reduced proliferation in the hippocampus of un-inoculated mice, suggesting that PrP plays a role in cell proliferation. We have demonstrated that prion disease and the resulting neuronal loss in the hippocampus increases neurogenesis (BrdU-labelled cells acquiring a neuronal phenotype) and also increases the numbers of proliferating astrocytes and microglia cells in the dentate gyrus of PrP over-expressing mice (tg37).

Type: Thesis (Doctoral)
Title: Neural stem cell recruitment in prion disease
Identifier: PQ ETD:593497
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/1446166
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