Lipids, oxidized lipids, oxidation-specific epitopes, and Age-related Macular Degeneration

Abstract

Age-related Macular Degeneration (AMD) is the leading cause of blindness among the elderly in western societies. While antioxidant micronutrient treatment is available for intermediate non-neovascular disease, and effective anti-vascular endothelial growth factor treatment is available for neovascular disease, treatment for early AMD is lacking due to an incomplete understanding of the early molecular events. The role of lipids, which accumulate in the macula, and their oxidation, has emerged as an important factor in disease development. These oxidized lipids can either directly contribute to tissue injury or react with amine on proteins to form oxidation-specific epitopes, which can induce an innate immune response. If inadequately neutralized, the inflammatory response from these epitopes can incite tissue injury during disease development. This review explores how the accumulation of lipids, their oxidation, and the ensuing inflammatory response might contribute to the pathogenesis of AMD. This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder .

Keywords: Age-related Macular Degeneration; Basal deposits; Bruch's membrane; Drusen; Oxidation-specific epitopes; Retinal pigmented epithelium (RPE); Very low-density lipoprotein (LDL).

Figure 1

The clinician and anatomist’s view of the macula. A. Fundus photograph of the macula. ON, optic nerve; F, foveola. B. Histological section of the macula with the internal limiting membrane (ILM), multi-layered ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), photoreceptor layer (PR), retinal pigmented epithelium (RPE), Bruch’s membrane (arrowheads), choriocapillaris (CC), and sclera (S). Bar=25μm.

Figure 2

A. Fundus image of a patient with large drusen (arrow). B. Fundus image of a patient with drusen (arrow) and RPE hypo- and hyper-pigmentary changes (*). ON, optic nerve.

Figure 3

Cartoon of Bruch’s membrane deposits with AMD. Basal laminar deposits (BLamD) develop between the RPE basal lamina (RPE BL) and the RPE cell while basal linear deposits (BLinD) develop in the inner collagenous layer (ICL). A druse occupies the subRPE space and is denoted by the gray line. The yellow dots represent lipoprotein deposits, which can be released from the RPE and transit in linear streaks (arrows) toward the choriocapillaris (CC). With age-related changes to the elastic layer (EL), lipoproteins collect at the inner surface of the elastic layer (EL) and accumulate toward the RPE.

Figure 4

Impaired Nrf2 signaling in AMD. Oxidative stress with reactive oxygen species (ROS) induce Nrf2 production and release from Keap1 with transit to the nucleus. After binding to antioxidant response elements in the promoters of antioxidant and cytoprotective genes with Maf proteins, antioxidant genes are upregulated. With aging and chronic oxidative stress, Nrf2 production and activity is reduced, and the antioxidant response is impaired, which contributes to RPE dysfunction.

Figure 5

OxPL and Lp(a) in the macula. A. Immunostaining for OxPL identified with E06 antibody in Bruch’s membrane and choroid including a druse (arrow). B. IgM control. C. Immunostaining for apo(a) in Bruch’s membrane and choroid including a large druse (arrow). D. IgG control. Ch, choroid. Bar=25μm.