Photoreceptor Cell Degeneration in Abcr –/– Mice

Li, Wu; Nagasaki, Taka; Sparrow, Janet R.

doi:10.1007/978-1-4419-1399-9_61

Cited by 69 publications

(79 citation statements)

References 22 publications

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“…4C). Importantly, the thinning of ONL that is indicative of reduced photoreceptor cell viability in albino Abca4 −/− mice (15,16,31) was less pronounced in the vitamin E-treated mice (Fig. 4D).…”

Section: Accumulation Of Bisretinoid In Dark-and Light-reared Albino mentioning

confidence: 96%

“…Marked bisretinoid accumulation is replicated not only in Abca4 null mutant mice (9,10) but also in mice deficient in retinol dehydrogenase-8 and dehydrogenase-12 (Rdh8; Rdh12) (11)(12)(13). In addition, the relationship between RPE lipofuscin accumulation and retinal disease is evidenced in the Abca4 mouse model by complement dysregulation, carbonyl-deposition, thickening of Bruch's membrane, and a progressive loss of photoreceptor cells (11,(14)(15)(16)(17).…”

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confidence: 97%

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Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Ueda

Zhao

Kim

et al. 2016

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

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111

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Adducts of retinaldehyde (bisretinoids) form nonenzymatically in photoreceptor cells and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin; these fluorophores are implicated in the pathogenesis of inherited and age-related macular degeneration (AMD). Here we demonstrate that bisretinoid photodegradation is ongoing in the eye. High-performance liquid chromatography (HPLC) analysis of eyes of dark-reared and cyclic light-reared wild-type mice, together with comparisons of pigmented versus albino mice, revealed a relationship between intraocular light and reduced levels of the bisretinoids A2E and A2-glycero-phosphoethanolamine (A2-GPE). Analysis of the bisretinoids A2E, A2-GPE, A2-dihydropyridinephosphatidylethanolamine (A2-DHP-PE), and all-trans-retinal dimerphosphatidylethanolamine (all-trans-retinal dimer-PE) also decreases in albino Abca4 −/− mice reared in cyclic light compared with darkness. In albino Abca4 −/− mice receiving a diet supplemented with the antioxidant vitamin E, higher levels of RPE bisretinoid were evidenced by HPLC analysis and quantitation of fundus autofluorescence; this effect is consistent with photooxidative processes known to precede bisretinoid degradation. Amelioration of outer nuclear layer thinning indicated that vitamin E treatment protected photoreceptor cells. Conversely, in-cage exposure to short-wavelength light resulted in reduced fundus autofluorescence, decreased HPLC-quantified A2E, outer nuclear layer thinning, and increased methylglyoxal (MG)-adducted protein. MG was also released upon bisretinoid photodegradation in cells. We suggest that the lower levels of these diretinal adducts in cyclic lightreared and albino mice reflect photodegradative loss of bisretinoid. These mechanisms may underlie associations among AMD risk, oxidative mechanisms, and lifetime light exposure.bisretinoid | visual cycle | retina | retinal pigment epithelium | macular degeneration

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Section: Accumulation Of Bisretinoid In Dark-and Light-reared Albino mentioning

confidence: 96%

mentioning

confidence: 97%

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Ueda

Zhao

Kim

et al. 2016

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

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111

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“…The likelihood that the dicarbonyl-MG was generated from RPE bisretinoid lipofuscin was shown by demonstrating that the levels increased in mice harboring increased bisretinoid and in mice that were pre-exposed to 430 nm light. In vivo carbonylation specific to RPE cells in Abca4 Ϫ/Ϫ mice was also shown by analysis of the RPE-specific protein Rpe65 in (27,43), photoreceptor cell loss is readily detectable in albino Abca4 Ϫ/Ϫ mice (24,25), and the retina is more susceptible to light damage (47). Abca4 Ϫ/Ϫ mice also exhibit increased expression of proteins of the complement system, excessive complement activation, down-regulation of complement inhibitory proteins, and Bruch's membrane thickening due to basal laminar deposits (64).…”

Section: Discussionmentioning

confidence: 87%

Correlations between Photodegradation of Bisretinoid Constituents of Retina and Dicarbonyl Adduct Deposition

Zhou

Ueda

Zhao

et al. 2015

Journal of Biological Chemistry

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Background:The origin of adduct-forming and cross-linking species in aging Bruch's membrane of the eye is unclear. Results: Mechanistic studies indicate links between photodegradation of bisretinoids of retinal pigment epithelial (RPE) cells and dicarbonyl adduct deposition. Conclusion: Dicarbonyl release from overlying RPE may be a factor in Bruch's membrane deposition. Significance: These processes could contribute to age-related macular degeneration.

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“…In support of this association are results showing that mice burdened with augmented bisretinoid formation monitored as elevated A2E and all-trans-retinal dimer, exhibit accentuated carbonyl-adduct deposition in Bruch's membrane, excessive complement activation, Bruch's membrane thickening due to basal laminar deposits, and accelerated loss of photoreceptor cells compared with WT mice (25)(26)(27)(28)(29)(30). Additionally, albino Abca4 −/− mice exhibit an increased susceptibility to retina light damage (31).…”

Section: What Are Vitamin A-aldehyde Adducts?mentioning

confidence: 80%

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics

Sparrow

2016

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

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Although currently available treatment options for age-related macular degeneration (AMD) are limited, particularly for atrophic AMD, the identification of predisposing genetic variations has informed clinical studies addressing therapeutic options such as complement inhibitors and anti-inflammatory agents. To lower risk of early AMD, recommended lifestyle interventions such as the avoidance of smoking and the intake of low glycemic antioxidant-rich diets have largely followed from the identification of nongenetic modifiable factors. On the other hand, the challenge of understanding the complex relationship between aging and cumulative damage leading to AMD has fueled investigations of the visual cycle adducts that accumulate in retinal pigment epithelial (RPE) cells and are a hallmark of aging retina. These studies have revealed properties of these compounds that provide insights into processes that may compromise RPE and could contribute to disease mechanisms in AMD. This work has also led to the design of targeted therapeutics that are currently under investigation.age-related macular degeneration | vitamin A-aldehyde adducts | bisretinoids | retinal pigment epithelium | photoreceptor cells Age-related macular degeneration (AMD) is a complex disorder that is predicted to have a growing impact on elderly populations. Although the cause of central vision loss in AMD is the progressive impairment of photoreceptor cells, the disease is generally thought to begin with dysfunctioning of retinal pigment epithelium (RPE) and adverse changes in subjacent Bruch's membrane (1, 2). The early stage of the disease is typically marked by extracellular accumulations (drusen) between RPE and Bruch's membrane. Progression to advanced disease is defined by delineated areas devoid of RPE and photoreceptor cell loss (atrophic AMD) and/or abnormal growth of blood vessels underneath RPE or within the subretinal space (neovascular AMD). AMD Risk FactorsAMD susceptibility is influenced by multiple factors of both genetic and environmental origin. Predisposing genetic factors account for 71% of the variation in disease risk among individuals (3). Currently, 52 independently associated genetic variants at 34 loci are known to account for ∼50% of AMD heritability (4). The genes implicated by these variants belong to multiple systems some of which are associated with the complement pathway, lipid metabolism, and maintenance of extracellular matrix (5, 6). Nevertheless, many individuals carrying risk variants do not develop AMD.Two loci, CFH (complement factor H; 1q31) and ARMS2/HTRA1 (age-related maculopathy susceptibility 2/high-temperature requirement factor A1; 10q26), make the greatest contribution to AMD risk. Variants at the ARMS2/HTRA1 and CFH loci significantly increase risk for progression to both the atrophic and neovascular forms of AMD, although the magnitude of the association of the ARMS2/HTRA1 risk allele is somewhat greater for the neovascular phenotype of late AMD, whereas CFH risk variants favor progression toward geogr...

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Photoreceptor Cell Degeneration in Abcr –/– Mice

Cited by 69 publications

References 22 publications

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Correlations between Photodegradation of Bisretinoid Constituents of Retina and Dicarbonyl Adduct Deposition

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics

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