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Age-related macular degeneration (AMD) is one of the leading causes of vision loss in the elderly. This disease involves oxidative stress burden in the retina leading to death of retinal pigment epithelial (RPE) cells and photoreceptors. The retina is susceptible to oxidative stress, in part due to high metabolic activity and high concentration of polyunsaturated fatty acids that undergo lipid peroxidation chain reactions. Antioxidant enzymes exist in the retina to combat this stress, including glutathione peroxidase 4 (GPX4). GPX4 specifically reduces oxidized lipids, protecting against lipid peroxidation-induced oxidative stress, which is noted in dry AMD. We hypothesize that Gpx4 knockout within the RPE will result in an environment of chronic oxidative stress yielding degeneration akin to AMD. C57BL/6J mice with a floxed Gpx4 gene were mated with Rpe65Cre/ER mice. Offspring containing Rpe65Cre ± alleles and either Gpx4 WT or Gpx4 fl/fl alleles were administered tamoxifen to induce Gpx4 knockout in Gpx4 fl/fl mice. At sequential timepoints, retinal phenotypes were assessed via in vivo imaging utilizing confocal scanning laser ophthalmoscopy and optical coherence tomography (OCT), and visual function was probed by electroretinography. Retinas were studied post-mortem by immunohistochemical analyses, electron microscopy, plastic sectioning, and quantitative polymerase chain reaction and Western analyses. The RPE-specific Gpx4 knockout model was validated via Western analysis indicating diminished GPX4 protein only within the RPE and not the neural retina. Following Gpx4 knockout, RPE cells became dysfunctional and died, with significant cell loss occurring 2 weeks post-knockout. Progressive thinning of the photoreceptor layer followed RPE degeneration and was accompanied by loss of visual function. OCT and light microscopy showed hyperreflective foci and enlarged, pigmented cells in and above the RPE layer. Electron microscopy revealed decreased mitochondrial cristae and loss of basal and apical RPE ultrastructure. Finally, there was increased carboxyethylpyrrole staining, indicating oxidation of docosahexaenoic acid, and increased levels of mRNAs encoding oxidative stress-associated genes in the RPE and photoreceptors. Overall, we show that RPE-localized GPX4 is necessary for the health of the RPE and outer retina, and that knockout recapitulates phenotypes of dry AMD.
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Because the selective estrogen receptor modulator tamoxifen was shown to be retina-protective in the light damage and rd10 models of retinal degeneration, the purpose of this study was to test whether tamoxifen is retina-protective in a model where retinal pigment epithelium (RPE) toxicity appears to be the primary insult: the sodium iodate (NaIO3) model. C57Bl/6J mice were given oral tamoxifen (in the diet) or the same diet lacking tamoxifen, then given an intraperitoneal injection of NaIO3 at 25 mg/kg. The mice were imaged a week later using optical coherence tomography (OCT). ImageJ with a custom macro was utilized to measure retinal thicknesses in OCT images. Electroretinography (ERG) was used to measure retinal function one week post-injection. After euthanasia, quantitative real-time PCR (qRT-PCR) was performed. Tamoxifen administration partially protected photoreceptors. There was less photoreceptor layer thinning in OCT images of tamoxifen-treated mice. qRT-PCR revealed, in the tamoxifen-treated group, less upregulation of antioxidant and complement factor 3 mRNAs, and less reduction in the rhodopsin and short-wave cone opsin mRNAs. Furthermore, ERG results demonstrated preservation of photoreceptor function for the tamoxifen-treated group. Cone function was better protected than rods. These results indicate that tamoxifen provided structural and functional protection to photoreceptors against NaIO3. RPE cells were not protected. These neuroprotective effects suggest that estrogen-receptor modulation may be retina-protective. The fact that cones are particularly protected is intriguing given their importance for human visual function and their survival until the late stages of retinitis pigmentosa. Further investigation of this protective pathway could lead to new photoreceptor-protective therapeutics.
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Modelos Animales de Enfermedad , Electrorretinografía , Yodatos , Ratones Endogámicos C57BL , Degeneración Retiniana , Tamoxifeno , Tomografía de Coherencia Óptica , Animales , Yodatos/toxicidad , Ratones , Tomografía de Coherencia Óptica/métodos , Tamoxifeno/farmacología , Degeneración Retiniana/prevención & control , Degeneración Retiniana/inducido químicamente , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Células Fotorreceptoras de Vertebrados/efectos de los fármacos , Células Fotorreceptoras de Vertebrados/patología , Rodopsina/metabolismo , Rodopsina/genética , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , ARN Mensajero/genética , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/metabolismo , Opsinas de Bastones/metabolismoRESUMEN
Sodium iodate (NaIO3) is a commonly used model for age-related macular degeneration (AMD), but its rapid and severe induction of retinal pigment epithelial (RPE) and photoreceptor degeneration can lead to the premature dismissal of potentially effective therapeutics. Additionally, little is known about how sex and age affect the retinal response to NaIO3. This study aims to establish a less severe yet reproducible regimen by testing low doses of NaIO3 while considering age- and sex-related effects, enabling a broader range of therapeutic evaluations. In this study, young (3-5 months) and old (18-24 months) male and female C57Bl/6J mice were given an intraperitoneal (IP) injection of 15, 20, or 25 mg/kg NaIO3. Damage assessment one week post-injection included in vivo imaging, histological examination, and qRT-PCR analysis. The results revealed that young mice showed no damage at 15 mg/kg IP NaIO3, with varying degrees of damage observed at 20 mg/kg. At 25 mg/kg, most young mice displayed widespread retinal damage, with females exhibiting less retinal thinning than males. In contrast, older mice at 20 and 25 mg/kg displayed a more patchy degeneration pattern, outer retinal undulations, and greater variability in degeneration than the young mice. The most effective model for minimizing damage while maintaining consistency utilizes young female mice injected with 25 mg/kg NaIO3. The observed sex- and age-related differences underscore the importance of considering these variables in research, aligning with the National Institutes of Health's guidance. While the model does not fully replicate the complexity of AMD, these findings enhance its utility as a valuable tool for testing RPE/photoreceptor protective or replacement therapies.
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Degeneración Macular , Degeneración Retiniana , Femenino , Masculino , Ratones , Animales , Retina/patología , Degeneración Retiniana/inducido químicamente , Degeneración Retiniana/patología , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/patología , Yodatos/toxicidad , Ratones Endogámicos C57BL , Epitelio Pigmentado de la Retina/patología , Modelos Animales de EnfermedadRESUMEN
In a previous report, a 39-year-old patient with high serum iron levels from hereditary hemochromatosis (HH) was diagnosed with a form of retinal degeneration called bull's eye maculopathy. This is atypical for patients with HH, so it was theorized that the low serum levels of ferroxidase ceruloplasmin (CP) of this patient coupled with the high iron levels led to the retinal degeneration. CP, by oxidizing iron from its ferrous to ferric form, helps prevent the oxidative damage caused by ferrous iron. To test this, a hepcidin knockout (KO) mouse model of HH was combined with Cp KO to test whether the combination would lead to more severe retinal degeneration. Monthly in vivo retinal images were acquired and, after 11â months, mice were euthanized for further analyses. Both heterozygous and homozygous Cp KO increased the rate and severity of retinal degeneration. These results demonstrate the protective role of CP, which is most likely owing to its ferroxidase activity. The findings suggest that CP levels may influence the severity of retinal degeneration, especially in individuals with high serum iron.
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Ceruloplasmina , Hemocromatosis , Degeneración Macular , Degeneración Retiniana , Animales , Ratones , Hemocromatosis/complicaciones , Hierro , Ratones NoqueadosRESUMEN
Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration, the leading cause of blindness in older adults, with retinal pigment epithelium (RPE) cells playing a key role. To better understand the cytotoxic mechanisms underlying oxidative stress, we used cell culture and mouse models of iron overload, as iron can catalyze reactive oxygen species formation in the RPE. Iron-loading of cultured induced pluripotent stem cell-derived RPE cells increased lysosomal abundance, impaired proteolysis and reduced the activity of a subset of lysosomal enzymes, including lysosomal acid lipase (LIPA) and acid sphingomyelinase (SMPD1). In a liver-specific Hepc (Hamp) knockout murine model of systemic iron overload, RPE cells accumulated lipid peroxidation adducts and lysosomes, developed progressive hypertrophy and underwent cell death. Proteomic and lipidomic analyses revealed accumulation of lysosomal proteins, ceramide biosynthetic enzymes and ceramides. The proteolytic enzyme cathepsin D (CTSD) had impaired maturation. A large proportion of lysosomes were galectin-3 (Lgals3) positive, suggesting cytotoxic lysosomal membrane permeabilization. Collectively, these results demonstrate that iron overload induces lysosomal accumulation and impairs lysosomal function, likely due to iron-induced lipid peroxides that can inhibit lysosomal enzymes.
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Sobrecarga de Hierro , Proteómica , Ratones , Animales , Estrés Oxidativo , Lisosomas/metabolismo , Hierro/metabolismo , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/patología , Células Epiteliales/metabolismo , Pigmentos Retinianos/metabolismo , Epitelio Pigmentado de la Retina/metabolismoRESUMEN
BACKGROUND/AIMS: Glucagon-like peptide-1 receptor (GLP-1R) agonists regulate blood glucose and are commonly used to treat type 2 diabetes mellitus. Recent work showed that treatment with the GLP-1R agonist NLY01 decreased retinal neuroinflammation and glial activation to rescue retinal ganglion cells in a mouse model of glaucoma. In this study, we used an insurance claims database (Clinformatics Data Mart) to examine whether GLP-1R agonist exposure impacts glaucoma risk. METHODS: A retrospective cohort of patients who initiated a new GLP-1R agonist was 1:3 age, gender, race, classes of active diabetes medications and year of index date matched to patients who initiated a different class of oral diabetic medication. Inverse probability of treatment weighting (IPTW) was used within a multivariable Cox proportional hazard regression model to test the association between GLP-1R agonist exposure and a new diagnosis of primary open-angle glaucoma, glaucoma suspect or low-tension glaucoma. RESULTS: Cohorts were comprised of 1961 new users of GLP-1R agonists matched to 4371 unexposed controls. After IPTW, all variables were balanced (standard mean deviation <|0.1|) between cohorts. Ten (0.51%) new diagnoses of glaucoma were present in the GLP-1R agonist cohort compared with 58 (1.33%) in the unexposed controls. After adjustment, GLP-1R exposure conferred a reduced hazard of 0.56 (95% CI: 0.36 to 0.89, p=0.01), suggesting that GLP-1R agonists decrease the risk for glaucoma. CONCLUSIONS: GLP-1R agonist use was associated with a statistically significant hazard reduction for a new diagnosis of glaucoma. Our findings support further investigations into the use of GLP-1R agonists in glaucoma prevention.
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Diabetes Mellitus Tipo 2 , Glaucoma de Ángulo Abierto , Animales , Ratones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/uso terapéutico , Estudios Retrospectivos , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Glaucoma de Ángulo Abierto/prevención & control , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/uso terapéuticoRESUMEN
Ophthalmic imaging instruments, including the confocal scanning laser ophthalmoscope and spectral-domain optical coherence tomography system, originally intended for revealing ocular microstructures in the human eye, have been deployed by vision researchers to evaluate the eyes of numerous small and large animal species for more than two decades. In this study, we have used these two instruments to obtain imaging data sequentially from the retinas of three prominent, widely used experimental mouse models to document changes induced by two contrasting vivarium lighting conditions. Mice studied include albino BALB/cJ and B6(Cg)-Tyrc-2J/J and pigmented C57Bl/6J. Mice were reared under dim light conditions until ~8 weeks of age where they underwent baseline imaging. Following, mice were returned to the dim vivarium or relocated to the top rack cage position in a standard vivarium. Mice were then followed for several months by ocular imaging to catalog the retinal dynamics as a function of long-term dim vs. elevated, standard vivarium lighting exposure levels. Upon exposure to elevated light levels, B6(Cg)-Tyrc-2J/J underwent similar changes as BALB/cJ in regard to photoreceptor outer segment shortening, photoreceptor layer proximal aspect hyperreflective changes, and the development of retinal infoldings and autofluorescent sub-retinal inflammatory monocyte infiltrate. Noteworthy, however, is that infoldings and infiltrate occurred at a slower rate of progression in B6(Cg)-Tyrc-2J/J vs. BALB/cJ. The photoreceptor outer nuclear layer thickness of BALB/cJ degenerated steadily following elevated light onset. In contrast, B6(Cg)-Tyrc-2J/J degeneration was unremarkable for many weeks before experiencing a noticeable change in the rate of degeneration that was concomitant with a plateau and decreasing trend in number of retinal infoldings and monocyte infiltrate. Pathological changes in C57Bl/6J mice were unremarkable for all imaging biomarkers assessed with exception to autofluorescent sub-retinal inflammatory monocyte infiltrate, which showed significant accumulation in dim vs. elevated light exposed mice following ~1 year of observation. These data were evaluated using Spearman's correlation and Predictive Power Score matrices to determine the best imaging optophysiological biomarkers for indicating vivarium light stress and light-induced photoreceptor degeneration. This study suggests that changes in proximal aspect hyperreflectivity, outer segment shortening, retinal infoldings and autofluorescent sub-retinal inflammatory monocyte infiltrate are excellent indicators of light stress and light-induced degeneration in albino B6(Cg)-Tyrc-2J/J and BALB/cJ mouse strains.
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Serum C-reactive protein (CRP), a marker of systemic inflammation, is associated with increased risk for numerous inflammation-driven chronic diseases. A prior longitudinal study showed that the Low Inflammatory Foods Everyday (LIFE) diet, which is rich in dark green leafy vegetables (DGLV), lowered CRP over a mean follow-up period of 6 months. In this retrospective study, we investigate whether patients who consume the LIFE diet or their regular diet plus one component of the LIFE diet (LIFE smoothie), experience reductions in high-sensitivity CRP (hsCRP) in 7 days. Sixteen patients in a community practice met inclusion criteria. Patient compliance was assessed by patient interviews and measurements of beta-carotene, which is abundant in DGLV. Following the interventions, CRP decreased in both the LIFE diet (-0.47 mg/L, P = .02) and smoothie groups (-1.2 mg/L, P = .04). No statistically significant difference in reduction was observed between groups (P = .18). Plasma beta-carotene increased in both groups (+23.2, P = .02; +20.6, P = .006, respectively). These findings suggest that the LIFE diet or a regular American diet supplemented with the LIFE smoothie may quickly reduce systemic inflammation and the risk of many chronic diseases.
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Age-related macular degeneration (AMD), the leading cause of irreversible blindness among Americans over 50, is characterized by dysfunction and death of retinal pigment epithelial (RPE) cells. The RPE accumulates iron in AMD, and iron overload triggers RPE cell death in vitro and in vivo. However, the mechanism of RPE iron accumulation in AMD is unknown. We show that high-fat-diet-induced obesity, a risk factor for AMD, drives systemic and local inflammatory circuits upregulating interleukin-1ß (IL-1ß). IL-1ß upregulates RPE iron importers and downregulates iron exporters, causing iron accumulation, oxidative stress, and dysfunction. We term this maladaptive, chronic activation of a nutritional immunity pathway the cellular iron sequestration response (CISR). RNA sequencing (RNA-seq) analysis of choroid and retina from human donors revealed that hallmarks of this pathway are present in AMD microglia and macrophages. Together, these data suggest that inflamed adipose tissue, through the CISR, can lead to RPE pathology in AMD.
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Degeneración Macular , Epitelio Pigmentado de la Retina , Tejido Adiposo/metabolismo , Humanos , Hierro/metabolismo , Degeneración Macular/metabolismo , Estrés Oxidativo , Retina/metabolismo , Epitelio Pigmentado de la Retina/metabolismoRESUMEN
Background: Ferritin is an iron-containing protein and acute-phase reactant, which may be elevated due to systemic iron overload or inflammation. Various diseases are associated with excess iron, but therapeutic iron chelation is suboptimal. Prior studies suggest that several plant phytochemicals possess iron-chelating properties, indicating that a plant-based diet may benefit patients with iron overload. Objectives: The aim was to investigate whether patients who consume a nutrient-dense, dark-green leafy vegetable-rich diet, called the Low Inflammatory Foods Everyday (LIFE) diet, experience reductions in ferritin concentrations. Methods: This was a retrospective study in which patients were intensively counseled to follow the LIFE diet. Compliance was assessed by patient interviews and serum B-carotene measurements. Primary outcomes included changes in ferritin, B-carotene, and C-reactive protein (CRP). Patients with elevated CRP concentrations at baseline were excluded in order to separate the impact of inflammation from iron overload on ferritin concentrations. Premenopausal women, who lose iron from menstruation, were also excluded. Results: Thirty-two patients met the inclusion criteria. The median follow-up was 183 d. Following the dietary intervention, ferritin decreased (-81 µg/L, P = 0.006) and B-carotene increased (46 µg/L, P < 0.0001), whereas CRP remained unchanged (-0.02 mg/L, P = 0.86). Adherent patients had greater reductions in ferritin compared with nonadherent patients (-138 µg/L vs. 15 µg/L, P = 0.001). Among all patients, there was an inverse relation between B-carotene and ferritin (-2.02, P = 0.03). Conclusions: The LIFE diet, or similar dark-green leafy vegetable-rich, whole-food plant-based diets, may benefit patients with disorders of iron overload and iron-induced oxidative stress.
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Iron accumulation has been implicated in degenerative retinal diseases. It can catalyze the production of damaging reactive oxygen species. Previous work has demonstrated iron accumulation in multiple retinal diseases, including age-related macular degeneration and diabetic retinopathy. In mice, systemic knockout of the ferroxidases ceruloplasmin (Cp) and hephaestin (Heph), which oxidize iron, results in retinal iron accumulation and iron-induced degeneration. To determine the role of Heph in the retina, we generated a neural retina-specific Heph knockout on a background of systemic Cp knockout. This resulted in elevated neural retina iron. Conversely, retinal ganglion cells had elevated transferrin receptor and decreased ferritin, suggesting diminished iron levels. The retinal degeneration observed in systemic Cp-/-, Heph-/- mice did not occur. These findings indicate that Heph has a local role in regulating neural retina iron homeostasis, but also suggest that preserved Heph function in either the RPE or systemically mitigates the degeneration phenotype observed in the systemic Cp-/-, Heph-/- mice.
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Degeneración Macular , Proteínas de la Membrana , Animales , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Homeostasis , Hierro/metabolismo , Degeneración Macular/genética , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Retina/metabolismoRESUMEN
Oxidative stress plays a central role in age-related macular degeneration (AMD). Iron, a potent generator of hydroxyl radicals through the Fenton reaction, has been implicated in AMD. One easily oxidized molecule is docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in photoreceptor membranes. Oxidation of DHA produces toxic oxidation products including carboxyethylpyrrole (CEP) adducts, which are increased in the retinas of AMD patients. In this study, we hypothesized that deuterium substitution on the bis-allylic sites of DHA in photoreceptor membranes could prevent iron-induced retinal degeneration by inhibiting oxidative stress and lipid peroxidation. Mice were fed with either DHA deuterated at the oxidation-prone positions (D-DHA) or control natural DHA and then given an intravitreal injection of iron or control saline. Orally administered D-DHA caused a dose-dependent increase in D-DHA levels in the neural retina and retinal pigment epithelium (RPE) as measured by mass spectrometry. At 1 week after iron injection, D-DHA provided nearly complete protection against iron-induced retinal autofluorescence and retinal degeneration, as determined by in vivo imaging, electroretinography, and histology. Iron injection resulted in carboxyethylpyrrole conjugate immunoreactivity in photoreceptors and RPE in mice fed with natural DHA but not D-DHA. Quantitative PCR results were consistent with iron-induced oxidative stress, inflammation, and retinal cell death in mice fed with natural DHA but not D-DHA. Taken together, our findings suggest that DHA oxidation is central to the pathogenesis of iron-induced retinal degeneration. They also provide preclinical evidence that dosing with D-DHA could be a viable therapeutic strategy for retinal diseases involving oxidative stress.
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Atrofia Geográfica , Sobrecarga de Hierro , Degeneración Macular , Degeneración Retiniana , Animales , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/efectos adversos , Atrofia Geográfica/inducido químicamente , Atrofia Geográfica/metabolismo , Atrofia Geográfica/patología , Humanos , Hierro/efectos adversos , Hierro/metabolismo , Sobrecarga de Hierro/complicaciones , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/metabolismo , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/metabolismo , Ratones , Estrés Oxidativo , Degeneración Retiniana/metabolismo , Epitelio Pigmentado de la Retina/metabolismoRESUMEN
Iron-induced oxidative stress can cause or exacerbate retinal degenerative diseases. Retinal iron overload has been reported in several mouse disease models with systemic or neural retina-specific knockout (KO) of homologous ferroxidases ceruloplasmin (Cp) and hephaestin (Heph). Cp and Heph can potentiate ferroportin (Fpn) mediated cellular iron export. Here, we used retina-specific Fpn KO mice to test the hypothesis that retinal iron overload in Cp/Heph DKO mice is caused by impaired iron export from neurons and glia. Surprisingly, there was no indication of retinal iron overload in retina-specific Fpn KO mice: the mRNA levels of transferrin receptor in the retina were not altered at 7-10-months age. Consistent with this, levels and localization of ferritin light chain were unchanged. To "stress the system", we injected iron intraperitoneally into Fpn KO mice with or without Cp KO. Only mice with both retina-specific Fpn KO and Cp KO had modestly elevated retinal iron levels. These results suggest that impaired iron export through Fpn is not sufficient to explain the retinal iron overload in Cp/Heph DKO mice. An increase in the levels of retinal ferrous iron caused by the absence of these ferroxidases, followed by uptake into cells by ferrous iron importers, is most likely necessary.
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Proteínas de Transporte de Catión , Sobrecarga de Hierro , Animales , Proteínas de Transporte de Catión/genética , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Hierro/metabolismo , Ratones , Ratones Noqueados , Retina/metabolismoRESUMEN
α-synuclein (α-syn) aggregation and accumulation drive neurodegeneration in Parkinson's disease (PD). The substantia nigra of patients with PD contains excess iron, yet the underlying mechanism accounting for this iron accumulation is unclear. Here, we show that misfolded α-syn activates microglia, which release interleukin 6 (IL-6). IL-6, via its trans-signaling pathway, induces changes in the neuronal iron transcriptome that promote ferrous iron uptake and decrease cellular iron export via a pathway we term the cellular iron sequestration response, or CISR. The brains of patients with PD exhibit molecular signatures of the IL-6-mediated CISR. Genetic deletion of IL-6, or treatment with the iron chelator deferiprone, reduces pathological α-syn toxicity in a mouse model of sporadic PD. These data suggest that IL-6-induced CISR leads to toxic neuronal iron accumulation, contributing to synuclein-induced neurodegeneration.
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Interleucina-6/metabolismo , Hierro/metabolismo , Neuronas/metabolismo , alfa-Sinucleína/toxicidad , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Femenino , Quelantes del Hierro/farmacología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Degeneración Nerviosa/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Transducción de Señal/efectos de los fármacos , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patologíaRESUMEN
Retinal pigment epithelium (RPE) dysfunction and atrophy occur in dry age-related macular degeneration (AMD), often leading to photoreceptor degeneration and vision loss. Accumulated oxidative stress during aging contributes to RPE dysfunction and degeneration. Here we show that the nuclear receptor REV-ERBα, a redox sensitive transcription factor, protects RPE from age-related degeneration and oxidative stress-induced damage. Genetic deficiency of REV-ERBα leads to accumulated oxidative stress, dysfunction and degeneration of RPE, and AMD-like ocular pathologies in aging mice. Loss of REV-ERBα exacerbates chemical-induced RPE damage, and pharmacological activation of REV-ERBα protects RPE from oxidative damage both in vivo and in vitro. REV-ERBα directly regulates transcription of nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream antioxidant enzymes superoxide dismutase 1 (SOD1) and catalase to counter oxidative damage. Moreover, aged mice with RPE specific knockout of REV-ERBα also exhibit accumulated oxidative stress and fundus and RPE pathologies. Together, our results suggest that REV-ERBα is a novel intrinsic protector of the RPE against age-dependent oxidative stress and a new molecular target for developing potential therapies to treat age-related retinal degeneration.
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Degeneración Macular , Degeneración Retiniana , Animales , Degeneración Macular/genética , Degeneración Macular/patología , Ratones , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares , Estrés Oxidativo/fisiología , Degeneración Retiniana/genética , Degeneración Retiniana/patología , Epitelio Pigmentado de la Retina/metabolismoRESUMEN
Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Dry AMD has unclear etiology and no treatment. Lipid-rich drusen are the hallmark of dry AMD. An AMD mouse model and insights into drusenogenesis are keys to better understanding of this disease. Chloride intracellular channel 4 (CLIC4) is a pleomorphic protein regulating diverse biological functions. Here we show that retinal pigment epithelium (RPE)-specific Clic4 knockout mice exhibit a full spectrum of functional and pathological hallmarks of dry AMD. Multidisciplinary longitudinal studies of disease progression in these mice support a mechanistic model that links RPE cell-autonomous aberrant lipid metabolism and transport to drusen formation.
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Canales de Cloruro/genética , Degeneración Macular/genética , Proteínas Mitocondriales/genética , Mutación/genética , Epitelio Pigmentado de la Retina/metabolismo , Animales , Muerte Celular , Canales de Cloruro/deficiencia , Modelos Animales de Enfermedad , Fondo de Ojo , Homeostasis , Metabolismo de los Lípidos , Degeneración Macular/diagnóstico por imagen , Degeneración Macular/fisiopatología , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Mitocondriales/deficiencia , Especificidad de Órganos/genética , Drusas Retinianas/complicaciones , Drusas Retinianas/diagnóstico por imagen , Drusas Retinianas/patología , Epitelio Pigmentado de la Retina/diagnóstico por imagen , Epitelio Pigmentado de la Retina/fisiopatología , Epitelio Pigmentado de la Retina/ultraestructura , Factores de Riesgo , Transcripción Genética , Visión Ocular/fisiologíaRESUMEN
Retinal inflammation underlies multiple prevalent ocular and neurological diseases. Similar inflammatory processes are observed in glaucomatous optic neuropathy, age-related macular degeneration, retinitis pigmentosa, posterior uveitis, Alzheimer's disease, and Parkinson's disease. In particular, human and animal studies have demonstrated the important role microglia/macrophages play in initiating and maintaining a pro-inflammatory environment in degenerative processes impacting vision. On the other hand, microglia have also been shown to have a protective role in multiple central nervous system diseases. Identifying the mechanisms underlying cell dysfunction and death is the first step toward developing novel therapeutics for these diseases impacting the central nervous system. In addition to reviewing recent key studies defining important mediators of retinal inflammation, with an emphasis on translational studies that bridge this research from bench to bedside, we also highlight a promising therapeutic class of medications, the glucagon-like peptide-1 receptor agonists. Finally, we propose areas where additional research is necessary to identify mechanisms that can be modulated to shift the balance from a neurotoxic to a neuroprotective retinal environment.
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Enfermedades Neurodegenerativas , Retinitis Pigmentosa , Animales , Encéfalo/metabolismo , Inflamación/metabolismo , Microglía/metabolismo , Células Mieloides/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Retina/metabolismo , Retinitis Pigmentosa/metabolismoRESUMEN
Chronic inflammation contributes to a number of chronic diseases and can be assessed with C-reactive protein (CRP). In this longitudinal retrospective chart review, we investigate whether patients intensively counseled to eat a specific diet high in dark green leafy vegetables, and thus high beta-carotene, have reductions in plasma high-sensitivity CRP (hsCRP). We term this the Low Inflammatory Foods Everyday (LIFE) diet. Forty-three patients in a community practice instructed to eat the LIFE diet met inclusion criteria. The CRP levels were measured at least twice over the course of up to a year. Adherence to the diet was objectively assessed by measurement of plasma beta-carotene, which is abundant in dark green leafy vegetables, and subjectively by serial interviews. The change in beta-carotene was inversely correlated with change in CRP (r = -0.68, P < .0001). Additionally, patients subjectively classified as adherent had higher beta-carotene (P < .0001) and lower CRP (P = .002) as compared with patients who were classified as nonadherent. These longitudinal findings suggest that adherence to the LIFE diet leads to increased beta-carotene and decreased CRP. Thus, this type of diet may reduce risk or severity of chronic diseases involving inflammation.
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Alzheimer's disease (AD) is associated with inner retina (nerve fiber and ganglion cell layers) thinning. In contrast, we have seen outer retina thinning driven by photoreceptor outer nuclear layer (ONL) thinning with antemortem optical coherence tomography (OCT) among patients considered to have a frontotemporal degeneration tauopathy (FTLD-Tau). Our objective was to determine if postmortem retinal tissue from FTLD-Tau patients demonstrates ONL loss observed antemortem on OCT. Two probable FTLD-Tau patients that were deeply phenotyped by clinical and genetic testing were imaged with OCT and followed to autopsy. Postmortem brain and retinal tissue were evaluated by a neuropathologist and ocular pathologist, respectively, masked to diagnosis. OCT findings were correlated with retinal histology. The two patients had autopsy-confirmed FTLD-Tau neuropathology and had antemortem OCT measurements showing ONL thinning (66.9 µm, patient #1; 74.9 µm, patient #2) below the 95% confidence interval of normal limits (75.1-120.7 µm) in our healthy control cohort. Postmortem, retinal tissue from both patients demonstrated loss of nuclei in the ONL, matching ONL loss visualized on antemortem OCT. Nuclei counts from each area of ONL loss (2 - 3 nuclei per column) seen in patient eyes were below the 95% confidence interval (4 - 8 nuclei per column for ONL) of 3 normal control retinas analyzed at the same location. Our evaluation of retinal tissue from FTLD-Tau patients confirms ONL loss seen antemortem by OCT. Continued investigation of ONL thinning as a biomarker that may distinguish FTLD-Tau from other dementias is warranted.