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Kei Takahashi, Miruto Tanaka, Shinsuke Nakamura, Masamitsu Shimazawa, Hideaki Hara; Progranulin knockout mice show the outer retinal abnormalities similar to advanced AMD. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1236.
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Chronic neuroinflammation of the retina is thought to involve in the etiology of age-related macular degeneration (AMD), but the mechanisms in detail are still not fully understood. Retinal microglia are the primary resident immune cell in the retina. Progranulin is a growth factor secreted from macrophages and microglial cells and plays an important role in controlling activation of these cells. Progranulin deficiency results in aberrant microglial activation and leads to neurodegeneration in the central nerve systems. The purpose of this study was to investigate the involvement of progranulin in the pathology of AMD.
Fundus photographs of 12- to 13- week old grn knockout (Grn−/−) mice and wild-type (Grn+/+) mice were taken with the retinal imaging microscope. By using C57BL/6J, Grn+/+, Grn+/− and Grn−/− mice, the localization and expression of progranulin were assessed by immunostaining and Western blotting with laser-induced choroidal neovascularization (CNV) model. The area of CNV fluorescein leakage was measured by fundus fluorescein angiography (FFA). The area of CNV was also quantified by RPE-choroid-sclera flatmounts perfused with FITC-dextran.
Funduscopy showed that all the Grn−/− mice had drusen-like nodular deposits in the deep layer of the retina, but were not present in age-matched Grn+/+ mice. Accordingly, we found that adult Grn−/− mice exhibited numerous F4/80-positive subretinal microglial cells adjacent to the retinal pigment epithelium (RPE), while these cells were absent in Grn+/+ mice. Retinal microglia or circulating macrophages were recruited to the injury site and expression level of progranulin in RPE-choroid complex was also increased during 3-7 days post-laser irradiation. At 14 days after laser injury, Grn+/+ mice ameliorated the pathological progression in experimental CNV model. In particular, average of FFA score in the Grn−/− mice significantly increased compared with that in Grn+/+.
These findings indicate that progranulin deficiency might be involved in the pathological progression of AMD via aberrant microglial activation in subretinal space. Therefore, progranulin might be the potential therapeutic target for AMD.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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