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

A lasered mouse model of retinal degeneration displays progressive outer retinal pathology providing insights into early geographic atrophy
A lasered mouse model of retinal degeneration displays progressive outer retinal pathology providing insights into early geographic atrophy
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.
2045-2322
Ibbett, Paul
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Goverdhan, Srinivas V.
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Pipi, Elena
3d4a3279-5001-4c32-a83a-7ba1f5980994
Chouhan, Joe Kirit
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Keeling, Eloise
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Angus, Elizabeth M.
a911c031-be90-4f89-9c65-405df5afb28f
Scott, Jenny
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Gatherer, Maureen
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Page, Anton
3b346d6a-855c-4838-a609-5eb40257e7c6
Teeling, Jessica
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
Lotery, Andrew
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Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd
Ibbett, Paul
bac07548-e35f-4f01-89c1-71b3404aa4e4
Goverdhan, Srinivas V.
9ae32d5a-5c82-48a4-962d-1ed8acc3991e
Pipi, Elena
3d4a3279-5001-4c32-a83a-7ba1f5980994
Chouhan, Joe Kirit
4468111f-65b2-4046-9860-70843616f83b
Keeling, Eloise
3207bbdb-d391-44af-8abc-a60c08dce45b
Angus, Elizabeth M.
a911c031-be90-4f89-9c65-405df5afb28f
Scott, Jenny
1695e9dd-d7fa-4e51-a842-d1d3caa29d4e
Gatherer, Maureen
b0aae216-21c4-4737-b042-865a65658f06
Page, Anton
3b346d6a-855c-4838-a609-5eb40257e7c6
Teeling, Jessica
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd

Ibbett, Paul, Goverdhan, Srinivas V., Pipi, Elena, Chouhan, Joe Kirit, Keeling, Eloise, Angus, Elizabeth M., Scott, Jenny, Gatherer, Maureen, Page, Anton, Teeling, Jessica, Lotery, Andrew and Ratnayaka, J. Arjuna (2019) A lasered mouse model of retinal degeneration displays progressive outer retinal pathology providing insights into early geographic atrophy. Scientific Reports, 9 (1), [7475]. (doi:10.1038/s41598-019-43906-z).

Record type: Article

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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Accepted/In Press date: 3 May 2019
e-pub ahead of print date: 16 May 2019
Published date: 16 May 2019

Identifiers

Local EPrints ID: 431187
URI: http://eprints.soton.ac.uk/id/eprint/431187
ISSN: 2045-2322
PURE UUID: b8a66550-0aa1-4fd0-9e2d-d0d2d7c29d5d
ORCID for Jessica Teeling: ORCID iD orcid.org/0000-0003-4004-7391
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305
ORCID for J. Arjuna Ratnayaka: ORCID iD orcid.org/0000-0002-1027-6938

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Date deposited: 24 May 2019 16:30
Last modified: 07 Oct 2020 02:03

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Contributors

Author: Paul Ibbett
Author: Srinivas V. Goverdhan
Author: Elena Pipi
Author: Eloise Keeling
Author: Elizabeth M. Angus
Author: Jenny Scott
Author: Maureen Gatherer
Author: Anton Page
Author: Jessica Teeling ORCID iD
Author: Andrew Lotery ORCID iD

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