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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Cole, Duncan Sean
Languages: English
Types: Doctoral thesis
Subjects: R1
Complement (C) activation and neuronal apoptosis occur in areas of active pathology in both neuroinflammatory and neurodegenerative disease. Little is currently known about how these two processes interact, and whether this causes further damage or promotes resolution and repair. The hypothesis of this thesis was that C modulates neuronal cell turnover in the central nervous system, with particular emphasis on its role in modulating apoptosis and handling of apoptotic cell debris. I have shown that apoptotic cells activated C more readily than controls, a change mediated via cleavage of CD46 from the cell membrane by matrix metalloproteases this resulted in increased phagocytosis and, in the early stages, increased C-mediated lysis, followed at later time points by decreased C-mediated killing. Cells surviving the apoptotic insult were also more resistant to C-mediated killing. CD59 was shed from apoptotic cells on blebs and as a soluble form, but cell surface levels were maintained late into apoptosis. The second part of the thesis examined the role of the C membrane attack complex (MAC) in modulating neuronal cell death. A reactive lysis system was developed, and neuronal cells were shown to possess recovery mechanisms on sublytic MAC attack. Neuronal cells subject to sublytic C displayed induced protection to lytic C, and this was shown to be MAC-independent. No effect of sublytic C was seen on neuronal apoptosis. The last part of the thesis used a kainic acid model of excitotoxicity in rats, and showed that the presence of the MAC did not have a significant role in modulating neuronal apoptotic death, but may have a role in sensitisation to seizures. Apoptotic neurons bound more C activation products and also stained brightly for CD59. These results demonstrate that C plays an important role in determining apoptotic cell fate, and when present at sublytic levels may promote neuronal survival and facilitate repair.
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