The Drusenlike Phenotype in Aging<i>Ccl2</i>-Knockout Mice Is Caused by an Accelerated Accumulation of Swollen Autofluorescent Subretinal Macrophages

Luhmann, Ulrich F O; Robbie, Scott; Munro, Peter; Barker, Susie E.; Durán, Yanaí; Luong, Vy; Fitzke, F.W.; Bainbridge, James; Ali, Robin R.; MacLaren, Robert E.

doi:10.1167/iovs.09-3462

Cited by 194 publications

(217 citation statements)

References 28 publications

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“…The authors detected macrophages and pigment in subretinal cells and concluded that they were the source of sub-RPE deposits. 56 We investigated choroidal vasculature using light and electron microscopy as well as FITC-dextran angiography because it is reported that reduction of choroidal vascularization may contribute to dry AMD. 2e4 Although FITC-dextran angiography is not a commonly used method to quantify choriocapillary density in naive animals, it is a well-accepted method to investigate choroidal neovascularization.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…Vacuolation (2/7 eyes) ( Figure 5f) and formation of multiple layers of hypopigmented retinal pigment cells (2/7 eyes) ( Figure 5g) were observed in the Rbp4 − / − retinal pigment epithelium. Large, irregular, macrophage-like cells (3/7 eyes) 24 appeared between the INL and retinal pigment epithelium in the regions where severe photoreceptor loss developed (2/7 eyes) (Figures 5g and h). One of the Rbp4 − / − mice had retinal structure collapse including disappearances of both retinal and choroidal layers in the peripheral retina (Figure 5i).…”

Section: Histological Comparison Of the Retinas Of Rbp4 +/+ Andmentioning

confidence: 99%

Severe ocular phenotypes in Rbp4-deficient mice in the C57BL/6 genetic background

Shen

Shi

Suzuki

et al. 2016

Laboratory Investigation

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Retinol-binding protein 4 (RBP4) is a specific carrier for retinol in the blood. In hepatocytes, newly synthesized RBP4 associates with retinol and transthyretin and is secreted into the blood. The ternary transthyretin-RBP4-retinol complex transports retinol in the circulation and delivers it to target tissues. Rbp4-deficient mice in a mixed genetic background (129xC57BL/6J) have decreased sensitivity to light in the b-wave amplitude on electroretinogram. Sensitivity progressively improves and approaches that of wild-type mice at 24 weeks of age. In the present study, we produced Rbp4-deficient mice in the C57BL/6 genetic background. These mice displayed more severe phenotypes. They had decreased a-and b-wave amplitudes on electroretinograms. In accordance with these abnormalities, we found structural changes in these mice, such as loss of the peripheral choroid and photoreceptor layer in the peripheral retinas. In the central retinas, the distance between the inner limiting membrane and the outer plexiform layer was much shorter with fewer ganglion cells and fewer synapses in the inner plexiform layer. Furthermore, ocular developmental defects of retinal depigmentation, optic disc abnormality, and persistent hyaloid artery were also observed. All these abnormalities had not recovered even at 40 weeks of age. Our Rbp4-deficient mice accumulated retinol in the liver but it was undetectable in the serum, indicating an inverse relation between serum and liver retinol levels. Our results suggest that RBP4 is critical for the mobilization of retinol from hepatic storage pools, and that such mobilization is necessary for ocular development and visual function.

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“…First was the supposition that the ∼25-μm diameter AF cells observed in the OS layer shown in Fig. 1A could represent infiltrating microglia/macrophages (40,41). Translocation of microglia/macrophages into the subretinal space is one of the features of retinal inflammation found in degenerating retinas (42,43).…”

Section: Tpm Noninvasively Images Autofluorescence (Af) Signals Frommentioning

confidence: 99%

“…Translocation of microglia/macrophages into the subretinal space is one of the features of retinal inflammation found in degenerating retinas (42,43). A second concern was that even though retinal infiltrating cells had been imaged by SLO as AF granules in Abca4 −/− Rdh8 −/− mice after light illumination (41,42), neither their fluorescence spectra nor their z location within the retina were known. Here we found increased numbers of SLO AF granules at day 3 that peaked at day 7 after light exposure [ Fig.…”

Section: Tpm Noninvasively Images Autofluorescence (Af) Signals Frommentioning

confidence: 99%

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Maeda

Palczewska

Golczak³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Atrophic age-related and juvenile macular degeneration are especially devastating due to lack of an effective cure. Two retinal cell types, photoreceptor cells and the adjacent retinal pigmented epithelium (RPE), reportedly display the earliest pathological changes. Abca4 −/− Rdh8 −/− mice, which mimic many features of human retinal degeneration, allowed us to determine the sequence of light-induced events leading to retinal degeneration. Using two-photon microscopy with 3D reconstruction methodology, we observed an initial strong retinoid-derived fluorescence and expansion of Abca4 −/− Rdh8 −/− mouse rod cell outer segments accompanied by macrophage infiltration after brief exposure of the retina to bright light. Additionally, light-dependent fluorescent compounds produced in rod outer segments were not transferred to the RPE of mice genetically defective in RPE phagocytosis. Collectively, these findings suggest that for light-induced retinopathies in mice, rod photoreceptors are the primary site of toxic retinoid accumulation and degeneration, followed by secondary changes in the RPE.

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The Drusenlike Phenotype in AgingCcl2-Knockout Mice Is Caused by an Accelerated Accumulation of Swollen Autofluorescent Subretinal Macrophages

Cited by 194 publications

References 28 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

Severe ocular phenotypes in Rbp4-deficient mice in the C57BL/6 genetic background

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

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