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  • Early retinal function deficit without prominent morphological changes in the R6/2 mouse model of Huntington's disease. 25469887

    Huntington's disease (HD) is an inherited neurodegenerative disorder that primarily affects the medium-size GABAergic neurons of striatum. The R6/2 mouse line is one of the most widely used animal models of HD. Previously the hallmarks of HD-related pathology have been detected in photoreceptors and interneurons of R6/2 mouse retina. Here we aimed to explore the survival of retinal ganglion cells (RGCs) and functional integrity of distinct retinal cell populations in R6/2 mice. The pattern electroretinography (PERG) signal was lost at the age of 8 weeks in R6/2 mice in contrast to the situation in wild-type (WT) littermates. This defect may be attributable to a major reduction in photopic ERG responses in R6/2 mice which was more evident in b- than a-wave amplitudes. At the age of 4 weeks R6/2 mice had predominantly the soluble form of mutant huntingtin protein (mHtt) in the RGC layer cells, whereas the aggregated form of mHtt was found in the majority of those cells from the 12-week-old R6/2 mice and onwards. Retinal astrocytes did not contain mHtt deposits. The total numbers of RGC layer cells, retinal astrocytes as well as optic nerve axons did not differ between 18-week-old R6/2 mice and their WT controls. Our data indicate that mHtt deposition does not cause RGC degeneration or retinal astrocyte loss in R6/2 mice even at a late stage of HD-related pathology. However, due to functional deficits in the rod- and cone-pathways, the R6/2 mice suffer progressive deficits in visual capabilities starting as early as 4 weeks; at 8 weeks there is severe impairment. This should be taken into account in any behavioral testing conducted in R6/2 mice.
    Document Type:
    Reference
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    Multiple
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    Multiple

  • Rescue of retinal degeneration by intravitreally injected adult bone marrow-derived lineage-negative hematopoietic stem cells. 15372100

    Inherited retinal degenerations afflict 1 in 3,500 individuals and are a heterogeneous group of diseases that result in profound vision loss, usually the result of retinal neuronal apoptosis. Atrophic changes in the retinal vasculature are also observed in many of these degenerations. While it is thought that this atrophy is secondary to diminished metabolic demand in the face of retinal degeneration, the precise relationship between the retinal neuronal and vascular degeneration is not clear. In this study we demonstrate that whenever a fraction of mouse or human adult bone marrow-derived stem cells (lineage-negative hematopoietic stem cells [Lin- HSCs]) containing endothelial precursors stabilizes and rescues retinal blood vessels that would ordinarily completely degenerate, a dramatic neurotrophic rescue effect is also observed. Retinal nuclear layers are preserved in 2 mouse models of retinal degeneration, rd1 and rd10, and detectable, albeit severely abnormal, electroretinogram recordings are observed in rescued mice at times when they are never observed in control-treated or untreated eyes. The normal mouse retina consists predominantly of rods, but the rescued cells after treatment with Lin- HSCs are nearly all cones. Microarray analysis of rescued retinas demonstrates significant upregulation of many antiapoptotic genes, including small heat shock proteins and transcription factors. These results suggest a new paradigm for thinking about the relationship between vasculature and associated retinal neuronal tissue as well as a potential treatment for delaying the progression of vision loss associated with retinal degeneration regardless of the underlying genetic defect.
    Document Type:
    Reference
    Product Catalog Number:
    AB5405
    Product Catalog Name:
    Anti-Opsin Antibody, Red/Green - (Anti-Opsin Antibody, Red/Green)

  • Retinal degeneration from oxidative damage. 16458197

    Paraquat, a herbicide that generates reactive oxygen species, has been used to probe the oxidative defense systems of lung. In this study, we investigated the effects of paraquat in the retina. There was no significant decline in electroretinogram (ERG) a- or b-wave amplitudes after intravitreous injection of 1 mul of 0.5 mM paraquat in C57BL/6 mice, but loss of ERG function occurred after injection of 0.75 or 1 mM paraquat. Histology in paraquat-injected eyes showed condensation of chromatin and thinning of the inner and outer nuclear layers indicating cell death, and terminal deoxynucleotidyl transferase-mediated duTP-biotinide end labeling demonstrated that one mechanism of cell death was apoptosis. Fluorescence in the retina and retinal pigmented epithelium after intraocular injection of paraquat followed by perfusion with hydroethidine indicated high levels of superoxide radicals, and oxidative damage was demonstrated by staining for acrolein and enzyme-linked immunosorbent assay for carbonyl adducts. Paraquat-induced damage to the outer nuclear layer was greater in BALB/c mice than in C57BL/6 mice, suggesting strain differences in the oxidative defense system of photoreceptors and/or other modifier genes. Intravitreous injection of paraquat provides a new model of oxidative damage-induced retinal degeneration that is likely to be useful for testing new antioxidant treatments.
    Document Type:
    Reference
    Product Catalog Number:
    S7165
    Product Catalog Name:
    ApopTag® Red In Situ Apoptosis Detection Kit - (ApopTag® Red In Situ Apoptosis Detection Kit)

  • Retinal organization in the retinal degeneration 10 (rd10) mutant mouse: a morphological and ERG study. 17111372

    Retinal degeneration 10 (rd10) mice are a model of autosomal recessive retinitis pigmentosa (RP), identified by Chang et al. in 2002 (Vision Res. 42:517-525). These mice carry a spontaneous mutation of the rod-phosphodiesterase (PDE) gene, leading to a rod degeneration that starts around P18. Later, cones are also lost. Because photoreceptor degeneration does not overlap with retinal development, and light responses can be recorded for about a month after birth, rd10 mice mimic typical human RP more closely than the well-known rd1 mutants. The aim of this study is to provide a comprehensive analysis of the morphology and function of the rd10 mouse retina during the period of maximum photoreceptor degeneration, thus contributing useful data for exploiting this novel model to study RP. We analyzed the morphology and survival of retinal cells in rd10 mice of various ages with quantitative immunocytochemistry and confocal microscopy; we also studied retinal function with the electroretinogram (ERG), recorded between P18 and P30. We found that photoreceptor death (peaking around P25) is accompanied and followed by dendritic retraction in bipolar and horizontal cells, which eventually undergo secondary degeneration. ERG reveals alterations in the physiology of the inner retina as early as P18 (before any obvious morphological change of inner neurons) and yet consistently with a reduced band amplification by bipolar cells. Thus, changes in the rd10 retina are very similar to what was previously found in rd1 mutants. However, an overall slower decay of retinal structure and function predicts that rd10 mice might become excellent models for rescue approaches.
    Document Type:
    Reference
    Product Catalog Number:
    MAB3073
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    Anti-G Protein Goα Antibody, clone 2A - (Anti-G Protein Goα Antibody, clone 2A)

  • Long-term retinal cone survival and delayed alteration of the cone mosaic in a transgenic mouse model of stargardt-like dystrophy (STGD3). 24334447

    To examine the pattern of cone degeneration in the retina of a transgenic mouse model of Stargartd-like dystrophy (STGD3).Investigations were performed on ELOVL4/TG1-2 transgenic (TG) mice and wild-type (WT) littermates from 1 to 24 months of age. Phenotypes were assessed by fundus imaging, fatty acid analysis, and electroretinogram (ERG) recording. Cone degeneration pattern was determined on retina whole mounts using immunohistochemistry and Voronoi domain analyses.Consistent with low transgene expression, photoreceptors degenerate very slowly. At 1 month, anatomical structure and fatty acid composition of the TG retina is comparable with WT. Rod loss appears at 2 months, exhibiting a central to peripheral gradient, and fundus defects are observed at 3 months. In contrast, cone morphology, distribution and function are still normal at 12 months. Cone loss becomes apparent at 15 months when the outer nuclear layer is reduced to 3 to 4 photoreceptor rows. This process starts at the center of the retina and affects cone subtypes similarly. Very few cones remain at 24 months, after all rods have disappeared (18 months). Quantitative studies focusing on cones expressing M-opsin show a net increase in Voronoi domains and a significant decrease in regularity indexes only beyond 15 months.Photoreceptor degeneration in this STGD3 mouse model follows the time course of a slow rod-cone dystrophy. The cone mosaic is preserved for almost 1 year after the onset of rod loss. This long delay provides an opportunity to examine rod-cone interactions during retinal degeneration and to test therapeutic effectiveness at protracting cone dysfunction.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
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    Multiple

  • Inner retinal change in a novel rd1-FTL mouse model of retinal degeneration. 26283925

    While photoreceptor loss is the most devastating result of inherited retinal degenerations such as retinitis pigmentosa, inner retinal neurons also undergo significant alteration. Detailing these changes has become important as many vision restorative therapies target the remaining neurons. In this study, the rd1-Fos-Tau-LacZ (rd1-FTL) mouse model was used to explore inner retinal change at a late stage of retinal degeneration, after the loss of photoreceptor nuclei. The rd1-FTL model carries a mutation in the phosphodiesterase gene, Pde6b, and an axonally targeted transgenic beta galactosidase reporter system under the control of the c-fos promoter. Retinae of transgenic rd1-FTL mice and control FTL animals aged 2-12 months were processed for indirect fluorescence immunocytochemistry. At 2 months of age, a time when the majority of photoreceptor nuclei are lost, there was negligible c-fos reporter (FTL) expression, however, from 4 months, reporter expression was observed to increase within subpopulations of amacrine and ganglion cells within the central retina. These areas of inner retinal FTL expression coincided with regions that contained aberrant Müller cells. Specifically, these cells exhibited reduced glutamine synthetase and Kir4.1 immunolabelling, whilst showing evidence of proliferative gliosis (increased cyclinD1 and glial fibrillary acidic protein expression). These changes were limited to distinct regions where cone photoreceptor terminals were absent. Overall, these results highlight that distinct areas of the rd1-FTL central retina undergo significant glial alterations after cone photoreceptor loss. These areas coincide with up-regulation of the c-fos reporter in the inner retina, which may represent a change in neuronal function/plasticity. The rd1-FTL mouse is a useful model system to probe changes that occur in the inner retina at later stages of retinal degeneration.
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    Reference
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    Multiple

  • Protection of retinal ganglion cells and retinal vasculature by Lycium barbarum polysaccharides in a mouse model of acute ocular hypertension. 23094016

    Acute ocular hypertension (AOH) is a condition found in acute glaucoma. The purpose of this study is to investigate the protective effect of Lycium barbarum polysaccharides (LBP) and its protective mechanisms in the AOH insult. LBP has been shown to exhibit neuroprotective effect in the chronic ocular hypertension (COH) experiments. AOH mouse model was induced in unilateral eye for one hour by introducing 90 mmHg ocular pressure. The animal was fed with LBP solution (1 mg/kg) or vehicle daily from 7 days before the AOH insult till sacrifice at either day 4 or day 7 post insult. The neuroprotective effects of LBP on retinal ganglion cells (RGCs) and blood-retinal-barrier (BRB) were evaluated. In control AOH retina, loss of RGCs, thinning of IRL thickness, increased IgG leakage, broken tight junctions, and decreased density of retinal blood vessels were observed. However, in LBP-treated AOH retina, there was less loss of RGCs with thinning of IRL thickness, IgG leakage, more continued structure of tight junctions associated with higher level of occludin protein and the recovery of the blood vessel density when compared with vehicle-treated AOH retina. Moreover, we found that LBP provides neuroprotection by down-regulating RAGE, ET-1, Aβ and AGE in the retina, as well as their related signaling pathways, which was related to inhibiting vascular damages and the neuronal degeneration in AOH insults. The present study suggests that LBP could prevent damage to RGCs from AOH-induced ischemic injury; furthermore, through its effects on blood vessel protection, LBP would also be a potential treatment for vascular-related retinopathy.
    Document Type:
    Reference
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    Multiple
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    Multiple

  • Inner retinal cell development is impaired in Smoky Joe chickens. 23571342

    Many different components of the retina can be affected by inherited degenerative diseases causing blindness. Currently, 5 different mutant strains of chicken have already been studied as potential models for inherited retinal degeneration; however, the potential for the blind strain of White Leghorns, called Smoky Joe (SJ), as a model remains unknown. Ocular symptoms observed within homozygous SJ birds show the birds have varying levels of blindness at hatch and by 8 wk posthatch are completely blind, but details about the development of the blindness are unclear (Salter et al., 1997). The objective of this study was to characterize the retinal development of blind and sighted SJ chicks during embryogenesis, and to monitor the numbers of the retinal cells with cell-type-specific markers. Blind SJ chicks showed less retinal cells throughout embryogenesis compared with sighted SJ chicks (P less than 0.0001). Based on the histological analysis, it was determined that amacrine cells within the inner nuclear layer were the most affected cell type, showing lower numbers in the blind SJ compared with the sighted; amacrine cell development was also delayed in the blind birds, beginning 2 d later than in sighted SJ birds. Photoreceptors were also scarcely detected within the blind SJ and potentially may be an additional target of developmental impairment. Further analysis on posthatch SJ will aid in determining degenerative characteristics of a fully developed retina and its cells.
    Document Type:
    Reference
    Product Catalog Number:
    MAB1585
    Product Catalog Name:
    Anti-Brn-3a Antibody, POU-domain protein, clone 5A3.2 - (Anti-Brn-3a Antibody, POU-domain protein, clone 5A3.2)

  • Severe retinal degeneration caused by a novel rhodopsin mutation. 19741247

    PURPOSE: To identify a new mouse mutation developing early-onset dominant retinal degeneration, to determine the causative gene mutation, and to investigate the underlying mechanism. METHODS: Retinal phenotype was examined by indirect ophthalmoscopy, histology, transmission electron microscopy, immunohistochemistry, Western blot analysis, and electroretinography. Causative gene mutation was determined by genomewide linkage analysis and DNA sequencing. Structural modeling was used to predict the impact of the mutation on protein structure. RESULTS: An ENU-mutagenized mouse line (R3), displaying attenuated retinal vessels and pigmented patches, was identified by fundus examination. Homozygous R3/R3 mice lost photoreceptors rapidly, leaving only a single row of photoreceptor nuclei at postnatal day 18. The a- and b-waves of ERG were flat in R3/R3 mice, whereas heterozygous R3/+ mice showed reduced amplitude of a- and b-waves. The R3/+ mice had a slower rate of photoreceptor cell loss than compound heterozygous R3/- mice with a null mutant allele. The R3 mutation was mapped and verified to be a rhodopsin point mutation, a c.553TC for a p.C185R substitution. The side chain of Arg(185) impacted on the extracellular loop of the protein. Mutant rhodopsin-C185R protein accumulated in the photoreceptor inner segments, cellular bodies, or both. CONCLUSIONS: Rhodopsin C185R mutation leads to severe retinal degeneration in R3 mutant mice. A dosage-dependent accumulation of misfolded mutant proteins likely triggers or stimulates the death of rod photoreceptors. The presence of a wild-type rhodopsin allele can delay the loss of photoreceptor cells in R3/+ mice.
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    Reference
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    Multiple
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    Multiple

  • Retinal remodeling in the Tg P347L rabbit, a large-eye model of retinal degeneration. 21681749

    Retinitis pigmentosa (RP) is an inherited blinding disease characterized by progressive loss of retinal photoreceptors. There are numerous rodent models of retinal degeneration, but most are poor platforms for interventions that will translate into clinical practice. The rabbit possesses a number of desirable qualities for a model of retinal disease including a large eye and an existing and substantial knowledge base in retinal circuitry, anatomy, and ophthalmology. We have analyzed degeneration, remodeling, and reprogramming in a rabbit model of retinal degeneration, expressing a rhodopsin proline 347 to leucine transgene in a TgP347L rabbit as a powerful model to study the pathophysiology and treatment of retinal degeneration. We show that disease progression in the TgP347L rabbit closely tracks human cone-sparing RP, including the cone-associated preservation of bipolar cell signaling and triggering of reprogramming. The relatively fast disease progression makes the TgP347L rabbit an excellent model for gene therapy, cell biological intervention, progenitor cell transplantation, surgical interventions, and bionic prosthetic studies. J. Comp. Neurol. 519:2713-2733, 2011. © 2011 Wiley-Liss, Inc.
    Document Type:
    Reference
    Product Catalog Number:
    AB5405
    Product Catalog Name:
    Anti-Opsin Antibody, Red/Green - (Anti-Opsin Antibody, Red/Green)