Person: Ramírez Sebastián, Ana Isabel
Universidad Complutense de Madrid
Faculty / Institute
Óptica y Optometría
Inmunología, Oftalmología y ORL
Now showing 1 - 10 of 72
PublicationMacular Thickness as a Potential Biomarker of Mild Alzheimer's Disease(Elsevier / American Academy of Ophthalmology, 2014-03-18) García Martín, Elena Salobrar; Rojas López, Blanca; Ramírez Sebastián, Ana Isabel; Hoz Montañana, Rosa de; Salazar Corral, Juan José; Yubero Pancorbo, Raquel; Gil, Pedro; Triviño Casado, Alberto; Ramirez Sebastian, Jose ManuelAlthough several postmortem findings in the retina of patients with Alzheimer's disease (AD) are available, new biomarkers for early diagnosis and follow-up of AD are still lacking. It has been postulated that the defects in the retinal nerve fiber layer (RNFL) may be the earliest sign of AD, even before damage to the hippocampal region that affects memory. This fact may reflect retinal neuronal-ganglion cell death and axonal loss in the optic nerve in addition to aging. PublicationOcular Vascular Changes in Mild Alzheimer’s Disease Patients: Foveal Avascular Zone, Choroidal Thickness, and ONH Hemoglobin Analysis(MDPI, 2020) García Martín, Elena Salobrar; Méndez Hernández, Carmen D.; Hoz Montañana, Rosa de; Ramírez Sebastián, Ana Isabel; López Cuenca, Inés; Fernández Arrabal, José A.; Rojas Lozano, Pilar; Wang, Surina; García Feijoo, Julián; Gil, Pedro; Salazar Corral, Juan José; Ramírez Sebastián, José ManuelIn Alzheimer’s disease (AD), vascular changes could be caused by amyloid beta (Aβ) aggregates replacing the contractile smooth musculature of the arteriole walls. These changes happen in the brain vascular network, but also in the eye, and are related to decreased vascular density and low blood flow. In patients with Alzheimer’s disease, thinning of the choroid and the retina has been shown. The aim of this prospective study was to assess the retinal and choroidal vascular systems, analyzing the choroidal thickness with optical coherence tomography (OCT), the foveal avascular zone (FAZ) with OCT-angiography (OCTA), and the optic nerve head (ONH) hemoglobin with the Laguna ONhE program, to evaluate which of the two ocular vascular systems shows earlier changes in mild AD patients. These patients, compared to controls, showed a significantly thinner choroid at all the analyzed points, with the exception of the temporal macula (at 1000 and 1500 µm from the fovea). On the other hand, the FAZ and ONH hemoglobin did not show significant differences. In conclusion, a thinner choroid was the main ocular vascular change observed in mild AD patients, while the retinal vessels were not yet affected. Therefore, choroidal thickness could be used an early biomarker in AD. PublicationMacroglial and retinal changes in hypercholesterolemic rabbits after normalization of cholesterol levels(Elsevier, 2006-09-26) Ramírez Sebastián, Ana Isabel; Salazar Corral, Juan José; Hoz Montañana, María Rosa de; Rojas López, María Blanca; Ruiz, Emilio; Tejerina Sánchez, Teresa; Ramirez Sebastian, Jose Manuel; Triviño Casado, AlbertoThis study evaluates hypercholesterolemic rabbits, examining the retinal changes in Müller cells and astrocytes as well as their variations after a period of normal blood-cholesterol values induced by a standard diet. New Zealand rabbits were divided into three groups: G0, fed a standard diet; G1A, fed a 0.5% cholesterol-enriched diet for 8 months; and G1B, fed as G1A followed by standard diet for 6 months. Eyes were processed for transmission electron microscopy and immunohistochemistry (GFAP). While G1B resembled G0 more than did G1A, they shared alterations with G1A: a) as in G1A, Müller cells were GFAP+, filled spaces left by axonal degeneration, formed glial scars and their nuclei were displaced to the nerve-fibre layer. The area occupied by the astrocytes associated with the nerve-fibre bundles (AANFB) and by perivascular astrocytes (PVA) in G1A and G1B was significantly lower than in controls. However, no significant differences in PVA were found between G1A and G1B. In G1B, type I PVA was absent and replaced by hypertrophic type II cells; b) Bruch's membrane (BM) was thinner in G1B than in G1A; c) the retinal pigment epithelium (RPE) cytoplasm contained fewer lipids in G1B than in G1A; d) in G1A and G1B choriocapillaris and retinal vessel showed alterations with respect to G0; e) cell death and axonal degeneration in the retina were similar in G1A and G1B. The substitution of a hyperlipemic diet by a standard one normalizes blood-lipid levels. However, the persistence of damage at retinal vessels and BM-RPE could trigger chronic ischemia. PublicationSearching for the Antioxidant, Anti-Inflammatory, and Neuroprotective Potential of Natural Food and Nutritional Supplements for Ocular Health in the Mediterranean Population(MDPI, 2021-05-28) Valero Velló, Mar; Peris Martínez, Cristina; García Medina, José Javier; Sanz González, Silvia María; Ramírez Sebastián, Ana Isabel; Fernández Albarral, José Antonio; Galarreta Mira, David; Zanón Moreno, Vicente; Casaroli Marano, Ricardo P.; Pinazo Durán, Mª DoloresAdherence to a healthy diet offers a valuable intervention to compete against the increas ing cases of ocular diseases worldwide, such as dry eye disorders, myopia progression, cataracts, glaucoma, diabetic retinopathy, or age macular degeneration. Certain amounts of micronutrients must be daily provided for proper functioning of the visual system, such as vitamins, carotenoids, trace metals and omega-3 fatty acids. Among natural foods, the following have to be considered for boosting eye/vision health: fish, meat, eggs, nuts, legumes, citrus fruits, nuts, leafy green vegetables, orange-colored fruits/vegetables, olives-olive oil, and dairy products. Nutritional supplements have received much attention as potential tools for managing chronic-degenerative ocular diseases. A systematic search of PubMed, Web of Science, hand-searched publications and historical archives were performed by the professionals involved in this study, to include peer-reviewed articles in which natural food, nutrient content, and its potential relationship with ocular health. Five ophthalmologists and two researchers collected the characteristics, quality and suitability of the above studies. Finally, 177 publications from 1983 to 2021 were enclosed, mainly related to natural food, Mediterranean diet (MedDiet) and nutraceutic supplementation. For the first time, original studies with broccoli and tigernut (chufa de Valencia) regarding the ocular surface dysfunction, macular degeneration, diabetic retinopathy and glaucoma were enclosed. These can add value to the diet, counteract nutritional defects, and help in the early stages, as well as in the course of ophthalmic pathologies. The main purpose of this review, enclosed in the Special Issue “Health Benefits and Nutritional Quality of Fruits, Nuts and Vegetables,” is to identify directions for further research on the role of diet and nutrition in the eyes and vision, and the potential antioxidant, anti-inflammatory and neuroprotec tive effects of natural food (broccoli, saffron, tigernuts and walnuts), the Mediterranean Diet, and nutraceutic supplements that may supply a promising and highly affordable scenario for patients at risk of vision loss. This review work was designed and carried out by a multidisciplinary group involved in ophthalmology and ophthalmic research and especially in nutritional ophthalmology. PublicationMicroglial Activation in the Retina of a Triple-Transgenic Alzheimer’s Disease Mouse Model (3xTg-AD)(MDPI, 2020-01-27) García Martín, Elena Salobrar; Rodríguez Neves, Ana C.; Ramírez Sebastián, Ana Isabel; Hoz Montañana, María Rosa de; Fernández Albarral, José Antonio; López Cuenca, Inés; Ramirez Sebastian, Jose Manuel; Ambrósio, Antonio Francisco; Salazar Corral, Juan JoséAlzheimer’s disease (AD) is the most common type of dementia in the world. The main biomarkers associated with AD are protein amyloid-β (Aβ) plaques and protein tau neurofibrillary tangles, which are responsible for brain neuroinflammation mediated by microglial cells. Increasing evidence has shown that the retina can also be affected in AD, presenting some molecular and cellular changes in the brain, such as microglia activation. However, there are only a few studies assessing such changes in the retinal microglia in animal models of AD. These studies use retinal sections, which have some limitations. In this study, we performed, for the first time in a triple-transgenic AD mouse model (3xTg-AD), a quantitative morphometric analysis of microglia activation (using the anti-Iba-1 antibody) in retinal whole-mounts, allowing visualization of the entire microglial cell, as well as its localization along the extension of the retina in different layers. Compared to age-matched animals, the retina of 3xTg-AD mice presents a higher number of microglial cells and a thicker microglial cell body area. Moreover, the microglia migrate, reorient, and retract their processes, changing their localization from a parallel to a perpendicular position relative to the retinal surface. These findings demonstrate clear microglia remodeling in the retina of 3xTg-AD mice. PublicationCPAMD8 loss-of-function underlies non-dominant congenital glaucoma with variable anterior segment dysgenesis and abnormal extracellular matrix(Springer-Verlag, 2020-04-09) Bonet Fernández, Juan Manuel; Aroca Aguilar, José Daniel; Corton Pérez, Marta; Ramírez Sebastián, Ana Isabel; Alexandre Moreno, Susana; García Antón, María Teresa; Salazar Corral, Juan José; Ferre Fernández, Jesús José; Atienzar Aroca, Raquel; Villaverde Montero, Cristina; Iancu, Ionut; Tamayo Durán, Alejandra; Méndez Hernández, Carmen Dora; Morales Fernández, Laura; Rojas López, Blanca; Ayuso García, Carmen; Coca Prados, Miguel; Martínez de la Casa, José María; García Feijoo, Julián; Escribano, JulioAbnormal development of the ocular anterior segment may lead to a spectrum of clinical phenotypes ranging from primary congenital glaucoma (PCG) to variable anterior segment dysgenesis (ASD). The main objective of this study was to identify the genetic alterations underlying recessive congenital glaucoma with ASD (CG-ASD). Next-generation DNA sequencing identified rare biallelic CPAMD8 variants in four patients with CG-ASD and in one case with PCG. CPAMD8 is a gene of unknown function and recently associated with ASD. Bioinformatic and in vitro functional evaluation of the variants using quantitative reverse transcription PCR and minigene analysis supported a loss-of-function pathogenic mechanism. Optical and electron microscopy of the trabeculectomy specimen from one of the CG-ASD cases revealed an abnormal anterior chamber angle, with altered extracellular matrix, and apoptotic trabecular meshwork cells. The CPAMD8 protein was immunodetected in adult human ocular fluids and anterior segment tissues involved in glaucoma and ASD (i.e., aqueous humor, non-pigmented ciliary epithelium, and iris muscles), as well as in periocular mesenchyme-like cells of zebrafish embryos. CRISPR/Cas9 disruption of this gene in F0 zebrafish embryos (96 hpf) resulted in varying degrees of gross developmental abnormalities, including microphthalmia, pharyngeal maldevelopment, and pericardial and periocular edemas. Optical and electron microscopy examination of these embryos showed iridocorneal angle hypoplasia (characterized by altered iris stroma cells, reduced anterior chamber, and collagen disorganized corneal stroma extracellular matrix), recapitulating some patients’ features. Our data support the notion that CPAMD8 loss-of-function underlies a spectrum of recessive CG-ASD phenotypes associated with extracellular matrix disorganization and provide new insights into the normal and disease roles of this gene. PublicationRetinal glial changes in Alzheimer's disease – A review(Elsevier, 2018-10-28) Fernández Arrabal, José A.; García Martín, Elena Salobrar; Martínez Páramo, Rebeca; Ramírez Sebastián, Ana Isabel; Hoz Montañana, María Rosa de; Ramírez Sebastián, José Manuel; Salazar Corral, Juan JoséAlzheimer's disease (AD) is a neurodegenerative dementia characterized by the deposition of extracellular β-amyloid (Aβ) plaques and the presence of neurofibrillary tangles. Until now, the techniques used to analyze these deposits have been difficult to access, invasive, and expensive. This leads us to consider new access routes to the central nervous system (CNS), allowing us to diagnose the disease before the first symptoms appear. Recent studies have shown that microglial and macroglial cell activation could play a role in the development of this disease. Glial cells in the CNS can respond to various damages, such as neurodegenerative pathologies, with morphological and functional changes. These changes are a common feature in neurodegenerative diseases, including AD. The retina is considered an extension of the CNS and has a population of glial cells similar to that of the CNS. When glial cells are activated, various molecules are released and changes in glial cell expression occur, which can be indicators of neuronal damage. The objective of this review is to compile the most relevant findings in the last 10 years relating to alterations in the eye in AD, and the role that glial cells play in the degenerative process in the retina in the context of neurodegeneration. PublicationCharacterization of Retinal Drusen in Subjects at High Genetic Risk of Developing Sporadic Alzheimer’s Disease: An Exploratory Analysis(MDPI, 2022-05-23) López Cuenca, Inés; García Martín, Elena Salobrar; Gil Salgado, Inés; Sánchez Puebla, Lídia; Elvira Hurtado, Lorena; Fernández Albarral, José Antonio; Ramírez Toraño, Federico; Barabash, Ana; Frutos Lucas, Jaisalmer de; Salazar Corral, Juan José; Ramirez Sebastian, Jose Manuel; Ramírez Sebastián, Ana Isabel; Hoz Montañana, María Rosa deHaving a family history (FH+) of Alzheimer’s disease (AD) and being a carrier of at least one ɛ4 allele of the ApoE gene are two of the main risk factors for the development of AD. AD and age-related macular degeneration (AMD) share one of the main risk factors, such as age, and characteristics including the presence of deposits (Aβ plaques in AD and drusen in AMD); however, the role of apolipoprotein E isoforms in both pathologies is controversial. We analyzed and characterized retinal drusen by optical coherence tomography (OCT) in subjects, classifying them by their AD FH (FH- or FH+) and their allelic characterization of ApoE ɛ4 (ApoE ɛ4- or ApoE ɛ4+) and considering cardiovascular risk factors (hypercholesterolemia, hypertension, and diabetes mellitus). In addition, we analyzed the choroidal thickness by OCT and the area of the foveal avascular zone with OCTA. We did not find a relationship between a family history of AD or any of the ApoE isoforms and the presence or absence of drusen. Subjects with drusen show choroidal thinning compared to patients without drusen, and thinning could trigger changes in choroidal perfusion that may give rise to the deposits that generate drusen PublicationRetinal Molecular Changes Are Associated with Neuroinflammation and Loss of RGCs in an Experimental Model of Glaucoma(MDPI, 2021-02-19) Fernández Arrabal, José A.; Salazar Corral, Juan José; Hoz Montañana, María Rosa de; Marco López, Eva María; Martín Sánchez, Beatriz; Flores Salguero, Elena; García Martín, Elena Salobrar; López Cuenca, Inés; Barrios Sabador, Vicente; Avilés Trigueros, Marcelino; Valiente Soriano, Francisco Javier; Miralles de Imperial-Ollero, Juan A.; Vidal Sanz, Manuel; Triviño Casado, Alberto; Ramirez Sebastian, Jose Manuel; López Gallardo, Meritxell; Ramírez Sebastián, Ana IsabelSignaling mediated by cytokines and chemokines is involved in glaucoma-associated neuroinflammation and in the damage of retinal ganglion cells (RGCs). Using multiplexed immunoassay and immunohistochemical techniques in a glaucoma mouse model at different time points after ocular hypertension (OHT), we analyzed (i) the expression of pro-inflammatory cytokines, anti-inflammatory cytokines, BDNF, VEGF, and fractalkine; and (ii) the number of Brn3a+ RGCs. In OHT eyes, there was an upregulation of (i) IFN-γ at days 3, 5, and 15; (ii) IL-4 at days 1, 3, 5, and 7 and IL-10 at days 3 and 5 (coinciding with downregulation of IL1-β at days 1, 5, and 7); (iii) IL-6 at days 1, 3, and 5; (iv) fractalkine and VEGF at day 1; and (v) BDNF at days 1, 3, 7, and 15. In contralateral eyes, there were (i) an upregulation of IL-1β at days 1 and 3 and a downregulation at day 7, coinciding with the downregulation of IL4 at days 3 and 5 and the upregulation at day 7; (ii) an upregulation of IL-6 at days 1, 5, and 7 and a downregulation at 15 days; (iii) an upregulation of IL-10 at days 3 and 7; and (iv) an upregulation of IL-17 at day 15. In OHT eyes, there was a reduction in the Brn3a+ RGCs number at days 3, 5, 7, and 15. OHT changes cytokine levels in both OHT and contralateral eyes at different time points after OHT induction, confirming the immune system involvement in glaucomatous neurodegeneration. PublicationBilateral early activation of retinal microglial cells in a mouse model of unilateral laser-induced experimental ocular hypertension(Elsevier, 2018-06) Hoz Montañana, Rosa de; Ramírez Sebastián, Ana Isabel; González Martín, Rosa; Ajoy, Daniel; Rojas López, Blanca; García Martín, Elena Salobrar; Valiente Soriano, Francisco Javier; Avilés Trigueros, Marcelino; Villegas Pérez, María Paz; Vidal Sanz, Manuel; Triviño Casado, Alberto; Ramirez Sebastian, Jose Manuel; Salazar Corral, Juan JoséThe immune system plays an important role in glaucomatous neurodegeneration. Retinal microglial reactivation associated with ganglion cell loss could reportedly contribute to the glaucoma progression. Recently we have described signs of microglia activation both in contralateral and ocular hypertension (OHT) eyes involving all retinal layers 15 days after OHT laser induction in mice. However, no works available have analyzed the microglial activation at earliest time points after OHT induction (24 h) in this experimental model. Thus, we seek to describe and quantify signs of microglia activation and differences depending on the retinal layer, 24 h after unilateral laser-induced OHT. Two groups of adult Swiss mice were used: age-matched control (naïve) and lasered. In the lasered animals, OHT eyes as well as contralateral eyes were analyzed. Retinal whole-mounts were immunostained with antibodies against Iba-1 and MHC-II. We quantified the number of microglial cells in the photoreceptor layer (OS), outer plexiform layer (OPL), and inner plexiform layer (IPL); the number of microglial vertical processes connecting the OPL and OS; the area of the retina occupied by Iba-1+ cells (Iba1-RA) in the nerve fiber layer-ganglion cell layer (NFL-GCL), the total arbor area of microglial cells in the OPL and IPL and; Iba-1+ cell body area in the OPL, IPL and NFL-GCL. In contralateral and OHT eyes the morphological features of Iba-1+ cell activation were: migration, enlargement of the cell body, higher degree of branching and reorientation of the processes, radial disposition of the soma and processes toward adjacent microglial plexuses, and presence of amoeboid cells acting as macrophages. These signs were more pronounced in OHT eyes. Most of Iba-1+ cells did not express MHC-II; rather, only dendritic and rounded cells expressed it. In comparison with naïve eyes, in OHT eyes and contralateral eyes no significant differences were found in the microglial cell number; but there was a significant increase in Iba1-RA. The total arbor area of microglial cells was significantly decreased in: i) OHT eyes with respect contralateral eyes and naïve-eyes in IPL; ii) OHT eyes with respect to naïve eyes in OPL. The number of microglial vertical processes connecting the OPL and OS were significantly increased in contralateral eyes compared with naïve-eyes and OHT eyes. In OPL, IPL and NFL-GCL, the cell body area of Iba-1+ cells was significantly greater in OHT eyes than in naïve and contralateral eyes, and greater in contralateral eyes than in naïve eyes. A non-proliferative microglial reactivation was detected both in contralateral eyes and in OHT eyes in an early time after unilateral laser-induced OHT (24 h). This fast microglial activation, which involves the contralateral eye, could be mediated by the immune system.