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

Abstract

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 810nm laser (1.9J/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.

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Identifiers

ORCID for Joe Kirit Chouhan: orcid.org/0000-0002-8067-5352

ORCID for Eloise Keeling: orcid.org/0000-0003-0399-359X

ORCID for Jessica Teeling: orcid.org/0000-0003-4004-7391

ORCID for Andrew Lotery: orcid.org/0000-0001-5541-4305

ORCID for J. Arjuna Ratnayaka: orcid.org/0000-0002-1027-6938

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