Declines in Arrestin and Rhodopsin in the Macula with Progression of Age-Related Macular Degeneration

Ethen, Cheryl M.; Feng, Xu; Olsen, Timothy W.; Ferrington, Deborah A.

doi:10.1167/iovs.04-0810

Cited by 20 publications

(20 citation statements)

References 23 publications

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“…Rhodopsin, a member of the G-proteinecoupled receptor family, is located in photoreceptor cells of the retina and a decline in rhodopsin content is observed with progression of AMD in humans. 37 Rhodopsin blot detected isoforms between 40 and 160 kDa in WT and Cd46 À/À mouse at 2 and 12 months of age ( Figure 5A). Densitometric analysis revealed a statistically significant reduction of total rhodopsin protein in Cd46 À/À mice at 12 months of age compared with that at 2 months when normalized to WT controls at both time points ( Figure 5B and Supplemental Table S8).…”

Section: Cd46 and Dry Amdmentioning

confidence: 99%

The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration–Like Phenotype

Lyzogubov

Bora

et al. 2016

The American Journal of Pathology

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In the mouse, membrane cofactor protein (CD46), a key regulator of the alternative pathway of the complement system, is only expressed in the eye and on the inner acrosomal membrane of spermatozoa. We noted that although Cd46 À/À mice have normal systemic alternative pathway activating ability, lack of CD46 leads to dysregulated complement activation in the eye, as evidenced by increased deposition of C5b-9 in the retinal pigment epithelium (RPE) and choroid. A knockout of CD46 induced the following cardinal features of human dry age-related macular degeneration (AMD) in 12-month-old male and female mice: accumulation of autofluorescent material in and hypertrophy of the RPE, dense deposits in and thickening of Bruch's membrane, loss of photoreceptors, cells in subretinal space, and a reduction of choroidal vessels. Collectively, our results demonstrate spontaneous age-related degenerative changes in the retina, RPE, and choroid of Cd46 À/À mice that are consistent with human dry AMD. These findings provide the exciting possibility of using Cd46 À/À mice as a convenient and reliable animal model for dry AMD. Having such a relatively straight-forward model for dry AMD should provide valuable insights into pathogenesis and a test model system for novel drug targets. More important, tissue-specific expression of CD46 gives the Cd46 À/À mouse model of dry AMD a unique advantage over other mouse models using knockout strains. Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in individuals >50 years of age in the United States and around the world. 1e5 This disease causes a progressive destruction of the macula, leading to the loss of central vision. AMD is a chronic degenerative process with multiple risk factors. 2,3,6e17 Nearly two million individuals in the United States alone are currently afflicted with AMD. This number is expected to grow in part because of increasing life expectancy. 5 Clinically, AMD is usually classified into two formsdnonexudative (dry type) and exudative (wet type). Although the dry form of AMD is more prevalent (approximately 85% of the cases) and a precursor to wet AMD, the fundamental processes underlying dry AMD are particularly not well understood. 2e4,6e10 Several agents to treat dry AMD are currently in the developmental stage. However, no effective treatment option is currently available. 11,12 Novel therapeutic targets for dry AMD need to be discovered.

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Section: Cd46 and Dry Amdmentioning

confidence: 99%

The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration–Like Phenotype

Lyzogubov

Bora

et al. 2016

The American Journal of Pathology

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“…The cone-driven a-wave reflects the phototransduction-induced stoppage of the dark current and changes in OFF bipolar cell activity. A potential contributor to higher a-wave amplitude could be a decrease in efficacy (or overall levels) of elements of the phototransduction inactivation system such as arrestin [34]. In addition, age-related delays in a-wave implicit times could reflect slower b-wave rise, therefore, allowing a further downward progression in the a-wave.…”

Section: Age-related Changes Under Photopic Adaptationmentioning

confidence: 99%

Differential changes in retina function with normal aging in humans

et al. 2011

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We evaluated the full field electroretinogram (ERG) to assess age-related changes in retina function in humans. ERG recordings were performed on healthy subjects with normal fundus appearance, lack of cataract and 20/20 acuity, aged 20-39 years (n = 27; mean age 25 ± 5, standard deviation), 40-59 years (n = 20; mean 53 ± 5), and 60-82 years (n = 18; mean 69 ± 5). Multiple ERG tests were applied, including light and dark-adapted stimulus-response function, dark adaptation and dynamic of recovery from a single bright flash under dark-adapted conditions. Changes in ERG properties were found in the oldest age group when compared with the two younger age groups. (1) The photopic hill effect was less pronounced. (2) Both photopic a-wave and b-wave amplitudes and implicit times were increased at high stimulus strengths. (3) Dark adaptation time was delayed for pure rod and L/M cone-driven responses, respectively. (4) Dark-adapted a-wave but not b-wave amplitudes were reduced, yielding higher B/A ratios. (5) Dark-adapted a- and b-waves implicit times were prolonged: there was a direct proportional correlation between minimal a-wave implicit times and age. (6) The dynamic of dark current recovery from a bright flash, under dark-adapted conditions, was transiently faster at intervals between 0.9 and 2 s. These results denote that aging of the healthy retina is accompanied by specific functional changes, which must be taken into account to optimally diagnose potential pathologies.

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“…Dissection of the sensory retina was performed as reported previously. 23 Criteria established by the MGS were used to determine the stage of AMD. 20 The stages of AMD are referred to as MGS1 (minimal or no AMD) through MGS4 (severe AMD), corresponding directly with the AREDS classification system.…”

Section: Grading Donor Eyesmentioning

confidence: 99%

“…23 In brief, a trephine punch of 8-mm diameter was centered over the macular area to separate the macula from the periphery. The neurosensory retina was then carefully peeled away from the RPE layer and homogenized (ϳ15 passes in a glass homogenizer with a Teflon pestle) in buffer containing 20% sucrose, 20 mM Tris-acetate (pH 7.2), 2 mM MgCl 2 , 10 mM glucose, and 2% CHAPS (3-([3-cholamidopropyl]dimethylammonio-2-hydroxy-1-propanesulfonate).…”

Section: Preparation Of Retinal Homogenatesmentioning

confidence: 99%

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The Proteome of Central and Peripheral Retina with Progression of Age-Related Macular Degeneration

Ethen

Reilly

Feng

et al. 2006

Invest. Ophthalmol. Vis. Sci.

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Declines in Arrestin and Rhodopsin in the Macula with Progression of Age-Related Macular Degeneration

Cited by 20 publications

References 23 publications

The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration–Like Phenotype

The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration–Like Phenotype

Differential changes in retina function with normal aging in humans

The Proteome of Central and Peripheral Retina with Progression of Age-Related Macular Degeneration

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