A lasered mouse model of retinal degeneration displays progressive outer retinal pathology providing insights into early geographic atrophy

• Published in: Scientific reports 2019-05, Vol.9 (1), p.7475, Article 7475
• Main Authors: Ibbett, Paul, Goverdhan, Srinivas V., Pipi, Elena, Chouhan, Joe K., Keeling, Eloise, Angus, Elizabeth M., Scott, Jenny A., Gatherer, Maureen, Page, Anton, Teeling, Jessica L., Lotery, Andrew J., Arjuna Ratnayaka, J.
• Format: Article
• Language: English
• Subjects: 13; 14/19; 14/28; 38/39; 692/699; 692/699/3161/1626; Age; Animal models; Animals; Atrophy; Cell activation; Complement activation; Disease Models, Animal; Drug discovery; Electron microscopy; Female; Geographic Atrophy - etiology; Geographic Atrophy - pathology; Humanities and Social Sciences; Inflammasomes; Infrared Rays - adverse effects; Lasers; Lesions; Macrophages; Macular degeneration; Mice; Mice, Inbred C57BL; mRNA; multidisciplinary; Oxidative stress; Pathology; Phagocytosis; Photoreception; Photoreceptors; Retina; Retina - diagnostic imaging; Retina - pathology; Retina - radiation effects; Retinal degeneration; Science; Science (multidisciplinary); Tomography, Optical Coherence
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-43906-z

Early stages of geographic atrophy (GA) age-related macular degeneration is characterised by the demise of photoreceptors, which precedes the loss of underlying retinal pigment epithelial (RPE) cells. Sight-loss due to GA has no effective treatment; reflecting both the complexity of the disease and the lack of suitable animal models for testing potential therapies. We report the development and characterisation of a laser-induced mouse model with early GA-like pathology. Retinas were lasered at adjacent sites using a 810 nm laser (1.9 J/spot), resulting in the development of confluent, hypopigmented central lesions with well-defined borders. Optical Coherence Tomography over 2-months showed progressive obliteration of photoreceptors with hyper-reflective outer plexiform and RPE/Bruch’s membrane (BrM) layers within lesions, but an unaffected inner retina. Light/electron microscopy after 3-months revealed lesions without photoreceptors, leaving the outer plexiform layer apposed to the RPE. We observed outer segment debris, hypo/hyperpigmented RPE, abnormal apical-basal RPE surfaces and BrM thickening. Lesions had wedge-shaped margins, extended zones of damage, activated Müller cells, microglial recruitment and functional retinal deficits. mRNA studies showed complement and inflammasome activation, microglial/macrophage phagocytosis and oxidative stress providing mechanistic insights into GA. We propose this mouse model as an attractive tool for early GA studies and drug-discovery.