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Title: Synaptic degeneration : a morphological study in a mouse model of prion disease
Author: Al-Malki, Hussain D.
ISNI:       0000 0004 2715 8836
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2012
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Early synaptic degeneration in prion disease has developed into a subject of interest, because it is thought that it may allow therapeutic intervention to prevent the neuronal death which is often observed at the late stage of the disease. However, the events behind the synaptic degeneration in prion disease, that may ultimately lead to neuronal death, are still unclear. Studying the morphology of neuronal components, namely synaptic boutons, axons, spines, dendrites and cell bodies, of the population of origin may help in understanding the neuropathology of prion disease. Intrahippocampal injection of murine modified scrapie (ME7 homogenate) provides a model of prion disease in vivo. Animals injected with ME7 were compared to control animals (injected with normal brain homogenate, NBH) and both groups were killed at 13, 16 and 19 weeks. At each time point, Biotinylated Dextran Amine (BDA) tracer was injected into the CA3 area of the hippocampus to reveal the morphology of neurons and their components during the disease progression, using both light and electron microscopy. The results showed that at 13 weeks, the number of synaptic boutons, which are distributed along the axons in the CA1 stratum radiatum, was significantly reduced, while most of the remainder were hypertrophied. This correlated with an increase in both the synaptic spacing along the axonal segments and the presence of abnormal swellings on the axons throughout the stratum radiatum. At 13 weeks, electron microscopic studies revealed vacuole-like structures in the synaptic boutons, which differed from actual autophagic or spongiform vacuoles. The results also showed a significant reduction in the number of dendritic spines on CA3 neurons, associated with a reduction in dendritic arborizations and length. Abnormal swellings were also seen in dendrites and occasionally in the cell bodies. Changes in CA3 cell body size were not observed until 16 weeks, when the soma area had reduced. The results indicate that changes in the morphology of synaptic boutons and dendritic spines were observed at an early time point, 13 weeks the fist observation time, and progressed with time. These results showed for the first time that there is a correlation between both synaptic bouton and spine loss in the neuron of origin, which may suggest that there is continual, simultaneous degeneration between the efferent and afferent components of neuron, leading to an early impairment of the neuronal communication within the brain. This suggests the notion that the loss of communication of the neuron at the early stage may lead to neuronal dysfunction and degeneration at the late stage of the disease. The results also suggest that the synaptic vacuoles may play a crucial role in the hypertrophy or degeneration of the remaining synapses. Additionally, it has been shown for the first time that astrocytes in ME7-animals express features of pathology and degeneration, suggesting that the astrocytes may be another target of PrPSc in prion disease. The combination of these findings has opened new avenues in the field of prion studies. The possible mechanisms behind these results are discussed.
Supervisor: Perry, Victor Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH301 Biology ; RB Pathology