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Jaimie Hoh Kam, Eva Lenassi, Matthew Pickering, Glen Jeffery; Complement C3 Deficiency Leads To Neurodegeneration And Retinal Dysfunction In An Age-Related Macular Degeneration Murine Model. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1009.
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Complement regulation is crucial for understanding disease. Complement component C3 (C3) is the central component of the complement system and a key inflammatory protein activated in age-related macular degeneration (AMD). AMD is associated with polymorphisms of complement factor H, which are thought to result in uncontrolled activation of C3. Consequently, inhibiting C3 activation is a target strategy in AMD treatment. Here we question this by examining an aged mouse model where both complement factor H and C3 have been knocked out (CFH-/-.C3-/-) compared with CFH-/- alone and normal aged C57Bl/6 wild type (WT) controls.
Visual functions of all mice were assessed using electroretinogram (ERG) and the eyes examined using a confocal scanning laser ophthalmoscope (SLO). At post-mortem, retinal structure was examined in resin section and with immunohistochemistry (IHC). Tissue was also imaged with a scanning electron microscope. Amyloid beta accumulation was assessed along the retinal pigment epithelium/Bruch’s membrane (RPE/BM) interface and on photoreceptor outer segments using IHC and Western blots.
CFH-/-.C3-/- accumulated amyloid beta in association with the RPE to a greater extent than the other groups. However, unlike the other groups they failed to accumulate this material on their outer segments. They also had significantly fewer outer retinal macrophages than the other groups. The ERG of CFH-/-.C3-/- animals displayed a more sever a-wave reduction than found in CFH-/- or WT animals, particularly at higher stimulus intensity, suggesting compromised rods and cones function. Histological analysis show significant photoreceptor loss in CFH-/-.C3-/- animals when compared with the other two groups.
It is thought that C3 impacts negatively on the retina. However, C3 deficiency in CFH knockout mice resulted in increased amyloid accumulation on RPE/BM and elevated photoreceptor loss leading to a reduced ERG responses. Contrary to expectation, these results point to a beneficial/protective role of C3 in this AMD mouse.
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