Limits...
Extreme retinal remodeling triggered by light damage: implications for age related macular degeneration.

Marc RE, Jones BW, Watt CB, Vazquez-Chona F, Vaughan DK, Organisciak DT - Mol. Vis. (2008)

Bottom Line: Across these zones, Müller cells manifest extreme changes in the definitive Müller cell tauQE signature, as well as CRALBP and arginine signals.If focal remodeling in LIRD accurately profiles late stage atrophic age-related macular degenerations, it augurs poorly for simple molecular interventions.Indeed, the LIRD profile in the SD rat manifests more similarities to advanced human atrophic AMD than most genetically or immunologically induced murine models of AMD.

View Article: PubMed Central - PubMed

Affiliation: Ophthalmology, University of Utah, John A. Moran Eye Center, Salt Lake City, UT 84132, USA. robert.marc@hsc.utah.edu

ABSTRACT

Purpose: Our objective was to comprehensively assess the nature and chronology of neural remodeling in retinal degenerations triggered by light-induced retinal damage (LIRD) in adult albino rodents. Our primary hypothesis is that all complete photoreceptor degenerations devolve to extensive remodeling. An hypothesis emergent from data analysis is that the LIRD model closely mimics late-stage atrophic age relared macular degeneration (AMD).

Methods: Sprague-Dawley (SD) rats received intense light exposures of varied durations and survival times ranging from 0 to 240 days. Remodeling was visualized by computational molecular phenotyping (CMP) of a small molecule library: 4-aminobutyrate (gamma), arginine (R), aspartate (D), glutamate (E), glutamine (Q), glutathione (J), glycine (G), and taurine (tau). This library was augmented by probes for key proteins such as rod opsin, cone opsin and cellular retinal binding protein (CRALBP). Quantitative CMP was used to profile 160 eyes from 86 animals in over 6,000 sections.

Results: The onset of remodeling in LIRD retinas is rapid, with immediate signs of metabolic stress in photoreceptors, the retinal pigmented epithelium (RPE), the choriocapillaris, and Müller cells. In particular, anomalous elevated aspartate levels appear to be an early stress marker in photoreceptors. After the stress phase, LIRD progresses to focal photoreceptor degeneration within 14 days and extensive remodeling by 60 days. RPE and choriocapillaris losses parallel Müller cell distal seal formation, with progressive neuronal migration, microneuroma evolution, fluid channel formation, and slow neuronal death. The remaining retina in advanced light damage can be classified as survivor, light damage (LD), or decimated zones where massive Müller cell and neuronal emigration into the choroid leaves a retina depleted of neurons and Müller cells. These zones and their transitions closely resemble human geographic atrophy. Across these zones, Müller cells manifest extreme changes in the definitive Müller cell tauQE signature, as well as CRALBP and arginine signals.

Conclusions: LIRD retinas manifest remodeling patterns of genetic retinal degeneration models, but involve no developmental complexities, and are ultimately more aggressive, devastating the remaining neural retina. The decimation of the neural retina via cell emigration through the perforated retina-choroid interface is a serious denouement. If focal remodeling in LIRD accurately profiles late stage atrophic age-related macular degenerations, it augurs poorly for simple molecular interventions. Indeed, the LIRD profile in the SD rat manifests more similarities to advanced human atrophic AMD than most genetically or immunologically induced murine models of AMD.

Show MeSH

Related in: MedlinePlus

Eruption of neurites into the choroid. Visualization: Quantitative gray-scale images of molecular signals displayed as intensity. Up arrows, remnant retina-choroid interface; horizontal arrows, neurons and neurites migrating in the choroid; angled arrows, eruption site. Each panel is 0.550 mm wide. A: Glutamate signals do not readily reveal any interruption in the MC seal. B: Glutamine signals generally indicate that the MC seal is confluent, though subtle variations in signal strength between the slanted arrows suggests an altered environment. C: Taurine signals do not readily reveal any interruption in the MC seal. D: Glycine signals indicate an eruption. Many glycinergic structures are located in the choroid distal to the arrows. E: γ-aminobutyric acid signals signals clearly indicate amacrine cell processes are entering the choroid. Sample metadata: SD Rat, age at LX 60 d, animal #P240–3L-48–240, left eye, 48 h LX, harvested at 240 days pLX, bloc code 6693, slide code 3528.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2375357&req=5

f9: Eruption of neurites into the choroid. Visualization: Quantitative gray-scale images of molecular signals displayed as intensity. Up arrows, remnant retina-choroid interface; horizontal arrows, neurons and neurites migrating in the choroid; angled arrows, eruption site. Each panel is 0.550 mm wide. A: Glutamate signals do not readily reveal any interruption in the MC seal. B: Glutamine signals generally indicate that the MC seal is confluent, though subtle variations in signal strength between the slanted arrows suggests an altered environment. C: Taurine signals do not readily reveal any interruption in the MC seal. D: Glycine signals indicate an eruption. Many glycinergic structures are located in the choroid distal to the arrows. E: γ-aminobutyric acid signals signals clearly indicate amacrine cell processes are entering the choroid. Sample metadata: SD Rat, age at LX 60 d, animal #P240–3L-48–240, left eye, 48 h LX, harvested at 240 days pLX, bloc code 6693, slide code 3528.

Mentions: Fluid channel evolution is restricted to the LIRD zone, but can be very severe, with survivor retina adjacent to the LIRD zone appearing completely normal (Figure 9). We have documented such channels in the transgenic P23H rat retina, in the RCS rat and many human RP retinas (unpublished data). The key feature that differentiates the LIRD model from all others is the eruption of processes from retinal neurons and ultimate emigration of Müller cells and neurons of all classes from the retina into the choroid (Figure 9 and Figure 10). Figure 9 illustrates early focal ruptures in the Müller cell-choroid interface and emigration of neurons from the retina. Elements with Müller cell-like high glutamine levels as well as neuronal processes (Figure 9) and neuronal groups of all signature classes can be found in the choroid. Most of these emigrant cells are fusiform and have clearly lost their characteristic shapes, but they retain their essential neurochemical profiles. Initially, small clusters of cells can be found in the choroid opposite remodeled Müller cells with extremely robust glutamine signals and a dense distal seal even at pLX 60 and abundantly at pLX 120 (Figure 11), implying that exit from the retina is actually an early process and that cells may translocate long distances. CRALBP is a distinctive marker for Müller cells and colocalization of CRALBP with glutamine reveals discrete patterns of Müller cell transformation. In survivor zones where rods persist (albeit shortened), Müller cell CRALBP-glutamine signatures are normal (Figure 11A). In the LD zone lacking photoreceptors, both CRALBP and glutamine levels are significantly elevated at the distal seal (Figure 11B). Figures 11C,D show that small clusters of emigrant cells with Müller cell CRALBP-glutamine signatures have formed above LD zones. However, in more dorsal retina (presumably the most severely damaged) emigration is so severe that over half the mass of the glutamine signal in the retina has moved to the choroid leaving a severely decimated retina. However, emigrant cells have severely down-regulated CRALBP expression (Figure 11E) despite preservation of the glutamine signal (Figure 11F).


Extreme retinal remodeling triggered by light damage: implications for age related macular degeneration.

Marc RE, Jones BW, Watt CB, Vazquez-Chona F, Vaughan DK, Organisciak DT - Mol. Vis. (2008)

Eruption of neurites into the choroid. Visualization: Quantitative gray-scale images of molecular signals displayed as intensity. Up arrows, remnant retina-choroid interface; horizontal arrows, neurons and neurites migrating in the choroid; angled arrows, eruption site. Each panel is 0.550 mm wide. A: Glutamate signals do not readily reveal any interruption in the MC seal. B: Glutamine signals generally indicate that the MC seal is confluent, though subtle variations in signal strength between the slanted arrows suggests an altered environment. C: Taurine signals do not readily reveal any interruption in the MC seal. D: Glycine signals indicate an eruption. Many glycinergic structures are located in the choroid distal to the arrows. E: γ-aminobutyric acid signals signals clearly indicate amacrine cell processes are entering the choroid. Sample metadata: SD Rat, age at LX 60 d, animal #P240–3L-48–240, left eye, 48 h LX, harvested at 240 days pLX, bloc code 6693, slide code 3528.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2375357&req=5

f9: Eruption of neurites into the choroid. Visualization: Quantitative gray-scale images of molecular signals displayed as intensity. Up arrows, remnant retina-choroid interface; horizontal arrows, neurons and neurites migrating in the choroid; angled arrows, eruption site. Each panel is 0.550 mm wide. A: Glutamate signals do not readily reveal any interruption in the MC seal. B: Glutamine signals generally indicate that the MC seal is confluent, though subtle variations in signal strength between the slanted arrows suggests an altered environment. C: Taurine signals do not readily reveal any interruption in the MC seal. D: Glycine signals indicate an eruption. Many glycinergic structures are located in the choroid distal to the arrows. E: γ-aminobutyric acid signals signals clearly indicate amacrine cell processes are entering the choroid. Sample metadata: SD Rat, age at LX 60 d, animal #P240–3L-48–240, left eye, 48 h LX, harvested at 240 days pLX, bloc code 6693, slide code 3528.
Mentions: Fluid channel evolution is restricted to the LIRD zone, but can be very severe, with survivor retina adjacent to the LIRD zone appearing completely normal (Figure 9). We have documented such channels in the transgenic P23H rat retina, in the RCS rat and many human RP retinas (unpublished data). The key feature that differentiates the LIRD model from all others is the eruption of processes from retinal neurons and ultimate emigration of Müller cells and neurons of all classes from the retina into the choroid (Figure 9 and Figure 10). Figure 9 illustrates early focal ruptures in the Müller cell-choroid interface and emigration of neurons from the retina. Elements with Müller cell-like high glutamine levels as well as neuronal processes (Figure 9) and neuronal groups of all signature classes can be found in the choroid. Most of these emigrant cells are fusiform and have clearly lost their characteristic shapes, but they retain their essential neurochemical profiles. Initially, small clusters of cells can be found in the choroid opposite remodeled Müller cells with extremely robust glutamine signals and a dense distal seal even at pLX 60 and abundantly at pLX 120 (Figure 11), implying that exit from the retina is actually an early process and that cells may translocate long distances. CRALBP is a distinctive marker for Müller cells and colocalization of CRALBP with glutamine reveals discrete patterns of Müller cell transformation. In survivor zones where rods persist (albeit shortened), Müller cell CRALBP-glutamine signatures are normal (Figure 11A). In the LD zone lacking photoreceptors, both CRALBP and glutamine levels are significantly elevated at the distal seal (Figure 11B). Figures 11C,D show that small clusters of emigrant cells with Müller cell CRALBP-glutamine signatures have formed above LD zones. However, in more dorsal retina (presumably the most severely damaged) emigration is so severe that over half the mass of the glutamine signal in the retina has moved to the choroid leaving a severely decimated retina. However, emigrant cells have severely down-regulated CRALBP expression (Figure 11E) despite preservation of the glutamine signal (Figure 11F).

Bottom Line: Across these zones, Müller cells manifest extreme changes in the definitive Müller cell tauQE signature, as well as CRALBP and arginine signals.If focal remodeling in LIRD accurately profiles late stage atrophic age-related macular degenerations, it augurs poorly for simple molecular interventions.Indeed, the LIRD profile in the SD rat manifests more similarities to advanced human atrophic AMD than most genetically or immunologically induced murine models of AMD.

View Article: PubMed Central - PubMed

Affiliation: Ophthalmology, University of Utah, John A. Moran Eye Center, Salt Lake City, UT 84132, USA. robert.marc@hsc.utah.edu

ABSTRACT

Purpose: Our objective was to comprehensively assess the nature and chronology of neural remodeling in retinal degenerations triggered by light-induced retinal damage (LIRD) in adult albino rodents. Our primary hypothesis is that all complete photoreceptor degenerations devolve to extensive remodeling. An hypothesis emergent from data analysis is that the LIRD model closely mimics late-stage atrophic age relared macular degeneration (AMD).

Methods: Sprague-Dawley (SD) rats received intense light exposures of varied durations and survival times ranging from 0 to 240 days. Remodeling was visualized by computational molecular phenotyping (CMP) of a small molecule library: 4-aminobutyrate (gamma), arginine (R), aspartate (D), glutamate (E), glutamine (Q), glutathione (J), glycine (G), and taurine (tau). This library was augmented by probes for key proteins such as rod opsin, cone opsin and cellular retinal binding protein (CRALBP). Quantitative CMP was used to profile 160 eyes from 86 animals in over 6,000 sections.

Results: The onset of remodeling in LIRD retinas is rapid, with immediate signs of metabolic stress in photoreceptors, the retinal pigmented epithelium (RPE), the choriocapillaris, and Müller cells. In particular, anomalous elevated aspartate levels appear to be an early stress marker in photoreceptors. After the stress phase, LIRD progresses to focal photoreceptor degeneration within 14 days and extensive remodeling by 60 days. RPE and choriocapillaris losses parallel Müller cell distal seal formation, with progressive neuronal migration, microneuroma evolution, fluid channel formation, and slow neuronal death. The remaining retina in advanced light damage can be classified as survivor, light damage (LD), or decimated zones where massive Müller cell and neuronal emigration into the choroid leaves a retina depleted of neurons and Müller cells. These zones and their transitions closely resemble human geographic atrophy. Across these zones, Müller cells manifest extreme changes in the definitive Müller cell tauQE signature, as well as CRALBP and arginine signals.

Conclusions: LIRD retinas manifest remodeling patterns of genetic retinal degeneration models, but involve no developmental complexities, and are ultimately more aggressive, devastating the remaining neural retina. The decimation of the neural retina via cell emigration through the perforated retina-choroid interface is a serious denouement. If focal remodeling in LIRD accurately profiles late stage atrophic age-related macular degenerations, it augurs poorly for simple molecular interventions. Indeed, the LIRD profile in the SD rat manifests more similarities to advanced human atrophic AMD than most genetically or immunologically induced murine models of AMD.

Show MeSH
Related in: MedlinePlus