Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD)

Abstract

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 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 photorecptors 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 β), 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.Corresponding author: Chi-Chao Chan, MD, 10 Center Drive, 10/10N103, NIH/NEI, Bethesda, MD 20892-1857. Tel: (301), 496-0417, Fax: (301) 402-8664, chanc@nei.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public AccessAuthor Manuscript Prog Retin Eye Res. Author ma...

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