Hoh Kam, M.J.;
Age-related changes in the retina and the risk factors leading to the onset of disease.
Doctoral thesis, UCL (University College London).
Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness in those over 50 years old in Western countries. It is a late-onset, neurodegenerative retinal disease, which is characterised by extracellular deposits containing amyloid beta peptides (Aβ) on the Bruch’s membrane. In half of AMD cases, polymorphisms in the gene encoding complement factor H (CFH) are associated with susceptibility to the disease. The aims of this thesis were; (1) to identify sites of Aβ accumulation in mouse ageing eye and macrophage up-regulation, (2) to investigate the effects of immunotherapy targeting Aβ as a potential treatment for AMD, (3) to examine how pathogens trigger retinal disease in CFH mice, (4) to determine whether the strategy of inhibiting complement component C3 (C3) and complement activation is beneficial or detrimental in CFH mice. I show that Aβ deposition increases with age and is accumulated on photoreceptor outer segment and on Bruch’s membrane. Systemic administration of an antibody targeting Aβ improved retinal pathology, by decreasing deposits and reducing the activation of C3. I also show that genetic mutation or polymorphism is not the only factor triggering the onset of AMD but also environmental factors such as pathogen load are also critical. C3 deficiency resulted in Aβ deposition and photoreceptor cell loss along with failure to activate macrophages, supporting a beneficial, neuroprotective role of C3 in the retina. Collectively these data show that inflammation is one factor that forms an umbrella for the onset and progression of AMD. However, inflammation is not always a negative phenomenon. Aβ deposition and pathogen load are factors that will trigger an inflammatory response in tissue and therefore ways to regulate inflammatory responses to physiological levels and subsequently removing the factor causing the inflammation without affecting the homeostasis of the tissue will be a step forward in treating AMD.
|Title:||Age-related changes in the retina and the risk factors leading to the onset of disease|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||Copyright restricted material has been removed from the digital copy of this thesis|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology|
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