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

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 (A?) 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 A? related pathology and develop a new therapeutic approaches.

SUBMITTER: Park SW

PROVIDER: S-EPMC5522269 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Park Sung Wook SW Im Sora S Jun Hyoung Oh HO Lee Kihwang K Park Young-Jun YJ Kim Jin Hyoung JH Park Woo Jin WJ Lee Young-Hoon YH Kim Jeong Hun JH

Oncotarget 20170601 25

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 hypoth ...[more]

PMID: 28467791

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Project description:Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness worldwide in the elderly population. The pathology of dry AMD consists of macular degeneration of photoreceptors and the RPE, lipofuscin (A2E) accumulation, and drusen formation. Mice have been widely used for generating models that simulate human AMD features for investigating the pathogenesis, treatment and prevention of the disease. Although the mouse has no macula, focal atrophy of photoreceptors and RPE, lipofuscin accumulation, and increased A2E can develop in aged mouse eyes. However, drusen are rarely seen in mice because of their simpler Bruch's membrane and different process of lipofuscin extrusion compared with humans. Thus, analyzing basal deposits at the ultrastructural level and understanding the ultrastructural pathologic differences between various mouse AMD models are critical to comprehending the significance of research findings and response to possible therapeutic options for dry AMD. Based on the multifactorial pathogenesis of AMD, murine dry AMD models can be classified into three groups. First, genetically engineered mice that target genes related to juvenile macular dystrophies are the most common models, and they include abcr(-/-) (Stargardt disease), transgenic ELOVL4 (Stargardt-3 dominant inheritary disease), Efemp1(R345W/R345W) (Doyne honeycomb retinal dystrophy), and Timp3(S156C/S156C) (Sorsby fundus dystrophy) mice. Other murine models target genes relevant to AMD, including inflammatory genes such as Cfh(-/-), Ccl2(-/-), Ccr2(-/-), Cx3cr1(-/-), and Ccl2(-/-)/cx3cr1(-/-), oxidative stress associated genes such as Sod1(-/-) and Sod2 knockdown, metabolic pathway genes such as neprilysin(-/-) (amyloid beta), transgenic mcd/mcd (cathepsin D), Cp(-/-)/Heph(-/Y) (ferroxidase ceruloplasmin/hepaestin, iron metabolism), and transgenic ApoE4 on high fat and high cholesterol diet (lipid metabolism). Second, mice have also been immunologically manipulated by immunization with carboxyethylpyrrole (CEP), an oxidative fragment of DHA found in drusen, and found to present with dry AMD features. Third, natural mouse strains such as arrd2/arrd2 (Mdm gene mutation) and the senescence accelerated mice (SAM) spontaneously develop features of dry AMD like photoreceptor atrophy and thickening of Bruch's membrane. All the aforementioned models develop retinal lesions with various features that simulate dry AMD lesions: focal photoreceptor degeneration, abnormal RPE with increased lipofuscin, basal infolding, decreased melanosomes and degeneration. However, Bruch's membrane changes are less common. Most mice develop retinal lesions at an older age (6-24 months, depending on the models), while the Ccl2(-/-)/cx3cr1(-/-) mice develop lesions by 4-6 weeks. Although murine models present various degrees of retinal and/or RPE degeneration, classical drusen is extremely rare. Using electron microscopy, small drusenoid deposits are found between RPE and Bruch's membrane in a few models including Efemp1(R345W/R345W), Ccl2(-/-)/cx3cr1(-/-), neprilysin(-/-), transgenic mcd/mcd, and ApoE4 transgenic mice on a high fat diet. High A2E levels are measured in the retinas of abcr(-/-), transgenic ELOVL4, and Ccl2(-/-)/cx3cr1(-/-) mice. In summary, murine models provide useful tools for studying AMD pathogenesis and evaluating novel therapies for this disease. This review compares the major dry AMD murine models and discusses retinal pathology at the ultrastructural level.

Dataset Information

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

Publications

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

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