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T. Yoshida, K. Ohno–Matsui, S. Ichinose, N. Iwata, T. Saido, T. Saito, T. Hisatomi, A. Kojima, I. Morita, M. Mochizuki; Subretinal Deposit Formation in Neprilysin Gene–disrupted Mice: An Important Role of Amyloid ß in the Pathogenesis of Age–related Macular Degeneration . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3013.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Drusens are extracellular deposits that lie beneath the basement membrane of the retinal pigment epithelium (RPE) and associated with increasing risk of developing choroidal neovascularization (CNV) in age–related macular degeneration (AMD). Recent proteome analysis demonstrated that amyloid ß (Aß) deposition was specific to drusen from eyes with AMD. We reported that Aß modulated the expression of angiogenesis–related factors in cultured RPE cells (#1800, ARVO 2004). In the present study, we investigated whether an increased deposition of Aß reproduces features of human AMD using mice lacking neprilysin (degrading enzyme of Aß) gene. Methods:Eyes from senescent neprilysin gene–disrupted and age–matched wild–type mice (27 months) were examined histopathologically. Immunoelectron microscopy was performed for detection of pathologically accumulated Aß. The expression of angiogenesis–related factors; VEGF and PEDF was detected using immunohistochemistry. Results:Light microscopy of paraffin sections from senescent neprilysin gene–disrupted mice showed an increased number of degenerated cells with vacuoles in RPE. In contrast, no such changes were visible in wild–type mice. Electron microscopic examination revealed basal laminar deposit as well as basal linear deposit beneath RPE layer. There was no migration or proliferation of choroidal endothelial cells or fibroblasts indicating the development of CNV, although modulation of VEGF and PEDF was detected in RPE immunohistochemically. Conclusions:This study demonstrated that an accumulation of Aß alone reproduced features characteristic to human AMD, such as atrophy of RPE cells and drusen formation. However, other factors such as breakdown of integrity of Bruch's membranes membrane than Aß deposition might be necessary to induce CNV.
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