Lack of Correlation Between the Spatial Distribution of A2E and Lipofuscin Fluorescence in the Human Retinal Pigment Epithelium

Higbee, Daniel; Anderson, David M.; Dahrouj, Mohammad; Grey, Angus C.; Gutierrez, Danielle B.; Koutalos, Yiannis; Schey, Kevin L.; Hanneken, Anne; Crouch, Rosalie K.

doi:10.1167/iovs.13-12250

Cited by 141 publications

(138 citation statements)

References 28 publications

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“…At the present point in RPE research, the mixture of compounds responsible for macular RPE AF is uncertain. As noted, prior literature suggests that a major macular fluorophore is A2E, but we now know that A2E is present here in small quantities only [18,26]. Hence, consideration must also be given to other candidates, including the known species just listed and others yet to be discovered.…”

Section: Application: Fluorophore Signal Recovery In the Human Rpementioning

confidence: 86%

“…The fluorescent bisretinoid A2E was long considered to be dominant in the RPE, because it was abundant and well characterized, and it was considered the major component across the entire RPE layer [17]. In 2013, imaging mass spectroscopy (IMS) revealed that A2E has strong regional variations in its tissue distribution, casting doubt on its role as a major disease initiator [18] and suggesting that additional compounds must be considered. There is extensive literature on bisretinoid biochemistry and the search for candidate RPE fluorophores [19,20].…”

Section: Application: Fluorophore Signal Recovery In the Human Rpementioning

confidence: 99%

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Simultaneous decomposition of multiple hyperspectral data sets: signal recovery of unknown fluorophores in the retinal pigment epithelium

Rjh

Post

Johri

et al. 2014

Biomed. Opt. Express

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Abstract:Upon excitation with different wavelengths of light, biological tissues emit distinct but related autofluorescence signals. We used nonnegative matrix factorization (NMF) to simultaneously decompose coregistered hyperspectral emission data from human retinal pigment epithelium/Bruch's membrane specimens illuminated with 436 and 480 nm light. NMF analysis was initialized with Gaussian mixture model fits and constrained to provide identical abundance images for the two excitation wavelengths. Spectra recovered this way were smoother than those obtained separately; fluorophore abundances more clearly localized within tissue compartments. These studies provide evidence that leveraging multiple coregistered hyperspectral emission data sets is preferential for identifying biologically relevant fluorophore information.

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Section: Application: Fluorophore Signal Recovery In the Human Rpementioning

confidence: 86%

Section: Application: Fluorophore Signal Recovery In the Human Rpementioning

confidence: 99%

Simultaneous decomposition of multiple hyperspectral data sets: signal recovery of unknown fluorophores in the retinal pigment epithelium

Rjh

Post

Johri

et al. 2014

Biomed. Opt. Express

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“…It was originally thought A2E correlated with AMD (Suter et al 2000), but later work found A2E primarily accumulated in the periphery of AMD eyes (Bhosale et al 2009), not in the macula. Furthermore, later work also demonstrated that lipofuscin only poorly predicted lesion spread in GA (Hwang et al 2006) and that the presence of A2E and lipofuscin did not even correlate with one another (Ablonczy et al 2013). Together, these data indicate A2E might be largely irrelevant to AMD and that visual cycle therapeutics like fenretinide would have little chance of having a protective effect in patients.…”

Section: Perspectives On Future Directionsmentioning

confidence: 99%

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

Narayanan

Kuppermann

2016

Handbook of Experimental Pharmacology

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“…only in the darkest zones of the retina [57]. When the same technology was applied to the eyes of ABCA4…”

Section: Phototoxicitymentioning

confidence: 99%

“…In addition, ABCA4 −/− mice who received vitamin E, a potent inhibitor of LB oxidation [44], displayed 54% more LBs than controls. Studies in humans, using luorescence microscopy for quantifying lipofuscin, and MALDI-IMS (high-resolution matrix assisted laser desorption-ionization imaging mass spectrometry) for detecting A2E showed that lipofuscin luorescence colocalized with A2Eonly in the darkest zones of the retina [57]. When the same technology was applied to the eyes of ABCA4…”

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confidence: 99%

Lipofuscin Accumulation into and Clearance from Retinal Pigment Epithelium Lysosomes: Physiopathology and Emerging Therapeutics

Nociari¹,

Kiss²,

Rodríguez-Boulan³

2017

Lysosomes - Associated Diseases and Methods to Study Their Function

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Photoreceptors undergo a constant renewal of their light sensitive outer segments (POSs). In the renewal process, 10% of the POS mass is daily phagocytized by the adjacent retinal pigment epithelium (RPE). POS contain vast amounts of 11-cis retinal and alltrans-retinal, two highly reactive vitamin A aldehydes that spontaneously dimerize into lipid bisretinoids (LBs) and accumulate into RPE lysosomes during phagocytosis. As LBs are refractory to lysosomal hydrolases and RPE cells do not divide, this accumulation is irreversible and results in the formation of lipofuscin granules. Lipofuscin accumulation is toxic for RPE cells through a variety of light-dependent and light-independent mechanisms. Beyond a threshold, RPE cells die resulting in secondary loss of overlying photoreceptors. Currently, there are no efective treatments for retinal disorders associated with genetic or age-associated LB accumulation, such as Stargardt disease and age-related macular degeneration (AMD). Thus, there is a great need for medical interventions. Here, we discuss the current understanding of lipofuscin's pathogenicity and the status of diferent strategies under development to promote LB elimination from RPE lysosomes.Keywords: lipofuscin, Stargardt, age-related macular degeneration (AMD), bisretinoids, retinal pigment epithelium (RPE), cyclodextrins, cellular clearance, TFEB, lysosome IntroductionTo understand the origin and consequences of the lysosomal accumulation of lipofuscin in the eye, a basic knowledge of retinal function and organization is required.© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The retinal pigment epithelium (RPE) in vertebrate's eyesLight entering the eye gets refracted by the cornea and lens on the neural retina, where photoreceptors (PR) convert photons into a cascade of chemical and electrical events that propagate to second-order (horizontal, bipolar, and amacrine cells) and third-order (ganglion cells) retinal neurons, which distribute this information to various visual centers of the brain through the ibers of the optic nerve. The bodies of PR cells, rods and cones, display three sectors (Figure 1): the outer segment, illed with stacks of disks densely packed with light-sensitive photopigment; the inner segment, illed with genetic, biosynthetic, and metabolic organelles Lysosomes -Associated Diseases and Methods to Study Their Function 4(nucleus, endoplasmic reticulum, Golgi complex, ribosomes, mitochondria); and the synaptic terminal that connects with bipolar neurons of the retina. In vertebrates, the retina is inverted in the sense that light passes through secondary and tertiary neuronal layers in the inner retina before reaching the rods and cones in the outer retina (Figure 1). Photoreceptors are metabolically very active cells that req...

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Lack of Correlation Between the Spatial Distribution of A2E and Lipofuscin Fluorescence in the Human Retinal Pigment Epithelium

Abstract: This report to our knowledge is the first description of the spatial distribution of A2E in the human RPE by imaging mass spectrometry. These data demonstrate that the accumulation of A2E is not responsible for the increase in lipofuscin fluorescence observed in the central RPE with aging.

Cited by 141 publications

References 28 publications

Simultaneous decomposition of multiple hyperspectral data sets: signal recovery of unknown fluorophores in the retinal pigment epithelium

Simultaneous decomposition of multiple hyperspectral data sets: signal recovery of unknown fluorophores in the retinal pigment epithelium

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

Lipofuscin Accumulation into and Clearance from Retinal Pigment Epithelium Lysosomes: Physiopathology and Emerging Therapeutics

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