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Katayoon Ebrahimi, Sonny Dike, Christian Gutierez, James Handa; C1q and Wnt Pathway Expression in Geographic Atrophy Model of ApoB100 Mutant Mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3202.
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© ARVO (1962-2015); The Authors (2016-present)
ApolipoproteinB100 particles, complement and cigarette smoke (CS) are involved in AMD. In the CNS, Wnt signaling is crucial for neuronal development. The classical complement through C1q, can mediate CNS synapse elimination. The purpose of this study was to determine if mice that express apoB100 and exposed to CS and high fat diet (HFD) develop AMD, and if C1q and WNT are expressed in the retina.
Two-mo old apoB100 mice were given a normal chow or HFD,exposed to air or CS for 2-6 months (n=5). Changes were evaluated by light and electron microscopy, and immunohistochemistry for C1q, C3, C4, LRP5/6, and FZ8.
We observed peripapillary and temporal geographic atrophy (GA) with neurosensory retinal and RPE atrophy in CS/HFD treated mice while controls (air, normal chow diet) were normal. The ONL from the treated mice were 6.8±0.8 rows thick, compared to control ONL 10.4±0.5; p=0.01. Photoreceptor inner and outer segments were shorter (POS length: 28.6 ± 1 vs 15.8 ± 3.3 μm, p=0.01), less dense with cell loss, and disorganized compared with control eyes. RPE clumping was observed at the edge of the GA. Intravascular thrombosis and recanalization in midchoroidal arteries was seen in all of CS/HFD treated mice. Ultrastructural changes included RPE basal infolding loss, and cytoplasmic vacuole accumulation. Some RPE were rounded and shrunk, with membrane blebbing, and nuclear fragmentation and lumpy condensed chromatin, which are characteristic of apoptosis. Strong punctuate C1q labeling in the OPL was seen after 2 mo of CS/HFD while C4 immunolabeling was not detected. C3 labeling was confined to retinal capillaries within the OPL and continuous within BM of treated mice only. Naito et al showed that C1q activates Wnt signaling and promotes aging-related phenotypes. Immunolabeling for WNT receptor LRP5/6 was more prominent in the INL, OPL, and photoreceptor inner segments of mice exposed to either CS or HFD compared to the control group. Mice exposed to CS/HFD had minimal labeling, coincident with photoreceptor degeneration and loss. FZ8, another WNT receptor, had more a wide labeling pattern that included the INL, IPL, ONL, OPL, and photoreceptor outer segments.
ApoB100 mice under stress develop peripapillary GA. We propose the possibility of a novel role for C1q mediated retinal synapse elimination and for Wnt pathway signaling in neurosensory retinal cell loss.
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