Contributions of age-related alterations of the retinal pigment epithelium and of glia to the AMD-like pathology in OXYS rats

Darya V Telegina,Nataliya G Kolosova,Oyuna S Kozhevnikova,Sergey I Bayborodin

doi:10.1038/srep41533

Abstract

Age-related macular degeneration (AMD) is a major cause of blindness in developed countries, and the molecular pathogenesis of early events of AMD is poorly understood. It is known that age-related alterations of retinal pigment epithelium (RPE) cells and of glial reactivity are early hallmarks of AMD. Here we evaluated contributions of the age-related alterations of the RPE and of glia to the development of AMD-like retinopathy in OXYS rats. We showed that destructive alterations in RPE cells are a primary change during the development of retinopathy in OXYS rats. Furthermore, a defect of retinal maturation and decreased immune function at the preclinical stage of retinopathy were observed in OXYS rats in addition to the impairment of RPE cell proliferation and of their capacity for division. At the active stage of the disease, the atrophic alterations increased, and reactive gliosis was observed when disease progressed, but immune function stayed weakened. Unexpectedly, we did not observe migration of microglia and macrophages into the photoreceptor layer. These results and the wide spectrum of age-related retinal alterations in humans as well as individual differences in the risk of AMD may be attributed to genetic factors and to differences in the underlying molecular events.

Highlights

Age-related macular degeneration (AMD) is a complex neurodegenerative disease with both genetic and environmental risk factors and remains a major cause of irreversible blindness affecting elderly people worldwide
To evaluate age-associated changes in the morphology of retinal pigment epithelium (RPE) cells, especially during the development of AMD-like retinopathy, we examined the RPE cell monolayer in Wistar and OXYS rats a) at the age of 20 days when retinal maturation is complete and signs of the disease are absent in the retina of OXYS rats; b) at the age of 3 months, i.e. in the period of active manifestation of clinical signs of retinopathy and c) at age 18 months: during the active disease progression in OXYS rats
We used OXYS rats as a model and demonstrated that the first aberrations in the RPE and glia appear at the age of 20 days when postnatal development of the rat retina finishes and there are no clinical signs of AMD-like retinopathy in OXYS rats

Summary

Introduction

Age-related macular degeneration (AMD) is a complex neurodegenerative disease with both genetic and environmental risk factors and remains a major cause of irreversible blindness affecting elderly people worldwide. Just as the dry form of human AMD, the initial alterations in the RPE cells later lead to atrophy of the choriocapillaris and a complete loss of photoreceptor cells in the OXYS retina by age 24 months[17,19,22,23] This animal model is successfully used to study the pathways and molecular alterations implicated in the development and progression of these disorders as well as to test new therapeutic interventions[21,22,23]. We investigated contributions of the age-related alterations of the RPE and of glia to the development of AMD-like pathology in OXYS rats We compared these rats with the control Wistar rats and OXYS rats at different stages of the disease, including pre-clinical stage

Methods

Results

Conclusion