Abstract
Genes that increase susceptibility to age-related macular degeneration (AMD) have been identified; however, since many individuals carrying these risk alleles do not develop disease, other contributors are involved. One additional factor, long implicated in the pathogenesis of AMD, is the lipofuscin of retinal pigment epithelium (RPE). The fluorophores that constitute RPE lipofuscin also serve as a source of autofluorescence (AF) that can be imaged by confocal laser ophthalmoscopy. The AF originating from lipofuscin is excited by the delivery of short wavelength (SW) light. A second autofluorescence is emitted from the melanin of RPE (and choroid) upon near-infrared (NIR-AF) excitation. SW-AF imaging is currently used in the clinical management of retinal disorders and the advantages of NIR-AF are increasingly recognized. Here we visit the damaging properties of RPE lipofuscin that could be significant when expressed on a background of genetic susceptibility. To advance interpretations of disease-related patterns of fundus AF in AMD, we also consider the photochemical and spectrophotometric features of the lipofuscin compounds responsible for generating the fluorescence emission.
Highlights
Age-related macular degeneration (AMD) is a complex disorder that is influenced by genetic and environmental factors; heritability is estimated to account for 45% to 71% of cases [1,2]
The propensity for bisretinoids to undergo photooxidative and photodegradative processes may underlie the decline in retinal pigment epithelium (RPE) lipofuscin fluorescence emission that has been observed in non-human primates during in vivo fluorescence imaging by adaptive optics scanning laser ophthalmoscopy [48,71], with cell culture models [72] and in non-cellular assays (Figure 4)
Interest in a role for RPE lipofuscin in age-related macular degeneration (AMD) stems from its age-related increase [10,11], an accumulation that is more pronounced in central retina [11], a propensity for adverse effects on RPE
Summary
Age-related macular degeneration (AMD) is a complex disorder that is influenced by genetic and environmental factors; heritability is estimated to account for 45% to 71% of cases [1,2]. RPE lipofuscin consists of a complex mixture of fluorophores that have been identified in by chromatography and mass spectrometry and characterized structurally; all of the known bisretinoid lipofuscin pigments have been detected in human eyes [26] (Figure 2) These fluorophores include the pyridinium-containing molecules A2-glycerophosphoethanolamine (A2-GPE) [27], A2E and isomers of A2E [28,29,30,31,32,33,34,35,36], dimers of all-trans-retinal having a cyclohexadiene head group (all-trans-retinal dimer) [33,37] and the associated protonated Schiff base conjugate [37] and the uncharged A2-DHP-PE (A2-dihydropyridine-phosphatidylethanolamine) [38]. The various bisretinoids of RPE lipofuscin have some common structural features (Figure 2) They present with a central six-carbon ring from which extend two polyene arms terminating in β ionone rings. Since these adducts of retinaldehyde are held together by covalent bonds, bisretinoids do not provide stores of retinoid for the visual cycle, as has been suggested [45]
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