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Chris Or, Jun Wang, Luba Kojic, William Jia, Max S Cynader, Jing Z Cui, Joanne A Matsubara; Expression of ADAMs (A Disintegrin and Metalloproteinase) 10 and 17 in Human Eyes and in Experimental Models of Age Related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2014;55(13):3460.
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ADAMs are crucial mediators in the proteolytic release of extracellular domains from membrane bound precursors. Recent studies support a role for ADAMs in mediating inflammation by the shedding of pro-inflammatory mediators. Chronic inflammation contributes to the development of AMD, but the role of ADAM10 and ADAM17 in this eye disease is unknown. We report the expression of ADAM10&17 in post-mortem eyes and in experimental models of AMD in which amyloid beta (Aβ), a drusen component, promotes pro-inflammatory events.
Young (<56) and old (>71) postmortem eyes were fixed and processed with standard methods. Long Evans rats underwent intravitreal injections of Aβ (1-40, 1.4 μg/μL) and eyes at Day 1, 4, 14 and 49 post-injection, were fixed and processed. Antibodies against ADAM10&17 were used at 1:200 and their immunohistochemical expression visualized. Next, mRNA abundances of ADAM10&17 were analyzed in ARPE19 or fetal hRPE by qRT-PCR. ADAM10&17 mRNA expression levels in fetal hRPE cells were also analyzed using qRT-PCR following Aβ (1μM) stimulation for 24h.
Moderate expression of ADAM10&17 was detected in RPE of old eyes and mild expression of ADAM 17 was noted in the RPE of young eyes. Older eyes with drusen demonstrated expression of ADAM10&17 within the drusenoid deposits. Choroidal macrophages also expressed ADAM10 in the old eyes. In vivo studies demonstrated that rodent eyes expressed ADAM10 at D1 and D4 and ADAM17 at D1 post-intravitreal injection of Aβ. In vitro studies demonstrated that transcriptional expression of ADAM17 was significantly increased by 20% (p=0.02), and a trend for increased ADAM10, in RPE following Aβ stimulation, The ARPE19 cell line and primary hRPE cells showed similar levels of mRNA abundance, with higher levels of ADAM17 compared to ADAM10.
Older postmortem eyes expressed higher levels of ADAM10&17, mostly in RPE and drusenoid deposits. The significance of this is currently unknown but the link between ADAMs and inflammation suggest an age-related relationship in ADAM expression that may contribute to AMD pathogenesis. Furthermore, the in vivo and in vitro results suggest that increased ADAM expression could be a result of Aβ stimulation, given a possible role of ADAMs in the removal of Aβ. Future work will allow us to clarify the role of ADAMs in the outer retina.
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