Dry age-related macular degeneration like pathology in aged 5XFAD mice: Ultrastructure and microarray analysis.

Sung Wook Park,Hyoung Oh Jun,Jin Hyoung Kim,Kihwang Lee,Sora Im,Young-Jun Park,Jeong Hun Kim,Woo Jin Park,Young-Hoon Lee

doi:10.18632/oncotarget.16967

Abstract

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. The two types of AMD are: dry and wet AMD. While laser-induced choroidal neovascularization has been used extensively in the studies of wet AMD, there is no established mouse model that fully recapitulates the cardinal features of dry AMD. A lack of appropriate mouse model for dry AMD has hampered the translational research on the pathogenesis of the disease and the development of therapeutic agents. We hypothesized that 5XFAD mice, an animal model for the study of Alzheimer’s disease, can be used as a mouse model for dry AMD with regard to the amyloid beta (Aβ) related pathology. In this study, the ultrastructure of the retinal pigment epithelium (RPE) of 5XFAD mice was analyzed using transmission electron microscopy. Of importance, the aged 5XFAD mice show ultrastructural changes in the RPE and Bruch’s membrane (BM) that are compatible with the cardinal features of human dry AMD, including a loss of apical microvilli and basal infolding of the RPE, increased BM thickness, basal laminar and linear deposits, and accumulation of lipofuscin granules and undigested photoreceptor outer segment-laden phagosomes. In microarray-based analysis, the RPE complex of the aged 5XFAD mice shows differential gene expression profiles consistent with dry AMD in the inflammation response, immune reaction pathway, and decreased retinol metabolism. Taken together, we suggest that aged 5XFAD mice can be used as a mouse model of dry AMD to study Aβ related pathology and develop a new therapeutic approaches.

Highlights

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly [1]
The aged 5XFAD mice show ultrastructural changes in the retinal pigment epithelium (RPE) and Bruch’s membrane (BM) that are compatible with the cardinal features of human dry AMD, including a loss of apical microvilli and basal infolding of the RPE, increased BM thickness, basal laminar and linear deposits, and accumulation of lipofuscin granules and undigested photoreceptor outer segment-laden phagosomes
The aged 5XFAD mice show ultrastructural changes in the RPE and BM that are compatible with the cardinal features of human dry AMD, including a loss of apical microvilli and basal infolding of the RPE, increased BM thickness, basal laminar and linear deposits, and accumulation of lipofuscin granules www.impactjournals.com/oncotarget and undigested photoreceptor rod outer segments (POS)-laden phagosomes

Summary

Introduction

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly [1]. In wet AMD, new blood vessels (known as choroidal neovascularization) grow into the macula and damage the retina. Dry AMD is characterized by the presence of drusen and atrophy of the retinal pigment epithelium (RPE) cells. While laserinduced choroidal neovascularization has been extensively used in the studies of wet AMD [2], there is no single mouse model that fully recapitulates the cardinal features of human dry AMD, mainly due to its multifactorial nature [3, 4]. Drusen, a hall-mark of dry AMD, is rarely found in mice. We aimed to validate the 5XFAD mouse, an animal model of Alzheimer’s disease (AD) that harbors five familial AD mutations, as a novel dry AMD mouse model that clearly shows amyloid beta deposits in the RPE

Objectives

Methods

Results

Conclusion