The ABCA1/G1 lipid-efflux pathway in the retinal pigment epithelium (RPE): a role in development of age-related macular degeneration (AMD)?

Abstract

Purpose : Genetic studies suggest an association between AMD and genes involved in lipid metabolism, such as the ATP-binding cassette transporter A1 (ABCA1). AMD affects the RPE, a tissue that daily handles large amounts of lipids coming from the phagocytosis of photoreceptor outer segments and/or from the blood. Since ABCA1 and its partner ABCG1 mediate lipid efflux, we investigated the function of the ABCA1/G1 pathway using an RPE-specific knockout (KO) mouse.

Methods : We analysed expression and localization of ABCA1 and ABCG1 in the retina with quantitative PCR and immunofluorescence. In order to understand the relevance of the pathway in vivo, we generated an RPE-specific Abca1;Abcg1 KO mouse (RPE^{ΔAbca1;Abcg1}) using the Cre-LoxP system. We analysed retinal morphology via fundus imaging and immunohistochemistry at different ages. Lipid composition was determined with a mass spectrometry-based lipidomic approach and retinal function measured via electroretinogram (ERG) recordings. Cre-negative littermates served as controls for all experiments.

Results : ABCA1 and ABCG1 were detected in all retinal layers, including the RPE. Non-invasive examination of the RPE^{ΔAbca1;Abcg1} mice revealed an abnormal fundus appearance at 8 weeks of age. Detailed analysis of the mutant RPE showed early and pronounced accumulation of lipid droplets and up to 50-fold increase in concentration of cholesteryl- and retinyl-ester species. The RPE of KO mice exhibited morphological alterations such as swelling of the cells, abnormal pigmentation and disorganized cytoplasm. In aged RPE^{ΔAbca1;Abcg1} mice (6-8 months), we observed retinal inflammation and RPE and photoreceptor degeneration. Functional consequences on the retina were measured as progressive reduction of scotopic and photopic ERGs in KO mice.

Conclusions : Our results support an important role of the ABCA1/G1 lipid efflux pathway for the maintenance of a healthy RPE and functional retina. RPE cells lacking Abca1 and Abcg1 may not be able to cope with the physiological lipid load originating from the daily internalization of shed photoreceptor outer segments and/or from the blood. Over time, lipid-filled RPE cells undergo cell death with consequent photoreceptor loss. We suggest that the ABCA1/G1 pathway might contribute to impaired lipid handling in the RPE of AMD patients.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.