16 results on '"Nicolas Belforte"'
Search Results
2. AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma
- Author
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Nicolas Belforte, Jessica Agostinone, Luis Alarcon-Martinez, Deborah Villafranca-Baughman, Florence Dotigny, Jorge L. Cueva Vargas, and Adriana Di Polo
- Subjects
Adenosine monophosphate-activated protein kinase ,Metabolic stress ,Mammalian target of rapamycin ,Glaucoma ,Neurodegeneration ,Neurology. Diseases of the nervous system ,RC346-429 ,Geriatrics ,RC952-954.6 - Abstract
Abstract Background The maintenance of complex dendritic arbors and synaptic transmission are processes that require a substantial amount of energy. Bioenergetic decline is a prominent feature of chronic neurodegenerative diseases, yet the signaling mechanisms that link energy stress with neuronal dysfunction are poorly understood. Recent work has implicated energy deficits in glaucoma, and retinal ganglion cell (RGC) dendritic pathology and synapse disassembly are key features of ocular hypertension damage. Results We show that adenosine monophosphate-activated protein kinase (AMPK), a conserved energy biosensor, is strongly activated in RGC from mice with ocular hypertension and patients with primary open angle glaucoma. Our data demonstrate that AMPK triggers RGC dendrite retraction and synapse elimination. We show that the harmful effect of AMPK is exerted through inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Attenuation of AMPK activity restores mTORC1 function and rescues dendrites and synaptic contacts. Strikingly, AMPK depletion promotes recovery of light-evoked retinal responses, improves axonal transport, and extends RGC survival. Conclusions This study identifies AMPK as a critical nexus between bioenergetic decline and RGC dysfunction during pressure-induced stress, and highlights the importance of targeting energy homeostasis in glaucoma and other neurodegenerative diseases.
- Published
- 2021
- Full Text
- View/download PDF
3. In utero Exposure to Valproic-Acid Alters Circadian Organisation and Clock-Gene Expression: Implications for Autism Spectrum Disorders
- Author
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Sarah Ferraro, Nuria de Zavalia, Nicolas Belforte, and Shimon Amir
- Subjects
autism spectrum disorder ,circadian rhythms ,valproic acid ,clock-gene ,rodent model ,rhythm disturbances ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder characterised by restrictive patterns of behaviour and alterations in social interaction and communication. Up to 80% of children with ASD exhibit sleep-wake cycle disturbances, emphasising the pressing need for novel approaches in the treatment of ASD-associated comorbidities. While sleep disturbances have been identified in ASD individuals, little has been done to assess the contribution of the circadian system to these findings. The objective of this study is to characterise circadian behaviour and clock-gene expression in a valproic acid (VPA)-induced animal model of autism to highlight perturbations potentially contributing to these disturbances. Male and female VPA-exposed offspring underwent circadian challenges, including baseline light-dark cycles, constant dark/light and light pulse protocols. Baseline analysis showed that VPA-exposed males, but not females, had a greater distribution of wheel-running behaviour across light-dark phases and a later activity offset (p < 0.0001), while controls showed greater activity confinement to the dark phase (p = 0.0256). Constant light analysis indicated an attenuated masking response and an increase in the number of days to reach arrhythmicity (p < 0.0001). A 1-h light pulse (150 lux) at CT 15 after 6 days of constant dark showed that both sexes exposed to VPA exhibited a lesser phase-shift when compared to controls (p = 0.0043). Immunohistochemical and western-blot assays reveal no alterations in retinal organisation or function. However, immunohistochemical assay of the SCN revealed altered expression of BMAL1 expression in VPA-exposed males (p = 0.0016), and in females (p = 0.0053). These findings suggest alterations within the core clockwork of the SCN and reduced photic-entrainment capacity, independent of retinal dysfunction. The results of this study shed light on the nature of circadian dysregulation in VPA-exposed animals and highlights the urgent need for novel perspectives in the treatment of ASD-associated comorbidities.
- Published
- 2021
- Full Text
- View/download PDF
4. Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease
- Author
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Marius Chiasseu, Luis Alarcon-Martinez, Nicolas Belforte, Heberto Quintero, Florence Dotigny, Laurie Destroismaisons, Christine Vande Velde, Fany Panayi, Caroline Louis, and Adriana Di Polo
- Subjects
Alzheimer’s disease ,Retinal ganglion cell ,Tau ,Axonal transport ,Neurodegeneration ,Neurology. Diseases of the nervous system ,RC346-429 ,Geriatrics ,RC952-954.6 - Abstract
Abstract Background Tau is an axon-enriched protein that binds to and stabilizes microtubules, and hence plays a crucial role in neuronal function. In Alzheimer’s disease (AD), pathological tau accumulation correlates with cognitive decline. Substantial visual deficits are found in individuals affected by AD including a preferential loss of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. At present, however, the mechanisms that underlie vision changes in these patients are poorly understood. Here, we asked whether tau plays a role in early retinal pathology and neuronal dysfunction in AD. Methods Alterations in tau protein and gene expression, phosphorylation, and localization were investigated by western blots, qPCR, and immunohistochemistry in the retina and visual pathways of triple transgenic mice (3xTg) harboring mutations in the genes encoding presenilin 1 (PS1M146 V), amyloid precursor protein (APPSwe), and tau (MAPTP301L). Anterograde axonal transport was assessed by intraocular injection of the cholera toxin beta subunit followed by quantification of tracer accumulation in the contralateral superior colliculus. RGC survival was analyzed on whole-mounted retinas using cell-specific markers. Reduction of tau expression was achieved following intravitreal injection of targeted siRNA. Results Our data demonstrate an age-related increase in endogenous retinal tau characterized by epitope-specific hypo- and hyper-phosphorylation in 3xTg mice. Retinal tau accumulation was observed as early as three months of age, prior to the reported onset of behavioral deficits, and preceded tau aggregation in the brain. Intriguingly, tau build up occurred in RGC soma and dendrites, while tau in RGC axons in the optic nerve was depleted. Tau phosphorylation changes and missorting correlated with substantial defects in anterograde axonal transport that preceded RGC death. Importantly, targeted siRNA-mediated knockdown of endogenous tau improved anterograde transport along RGC axons. Conclusions Our study reveals profound tau pathology in the visual system leading to early retinal neuron damage in a mouse model of AD. Importantly, we show that tau accumulation promotes anterograde axonal transport impairment in vivo, and identify this response as an early feature of neuronal dysfunction that precedes cell death in the AD retina. These findings provide the first proof-of-concept that a global strategy to reduce tau accumulation is beneficial to improve axonal transport and mitigate functional deficits in AD and tauopathies.
- Published
- 2017
- Full Text
- View/download PDF
5. The glial cell modulator ibudilast attenuates neuroinflammation and enhances retinal ganglion cell viability in glaucoma through protein kinase A signaling
- Author
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Jorge L. Cueva Vargas, Nicolas Belforte, and Adriana Di Polo
- Subjects
Gliosis ,Neurodegeneration ,cAMP Phosphodiesterase inhibitor ,Optic nerve ,Ocular hypertension ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Glaucoma is a neurodegenerative disease and the leading cause of irreversible blindness worldwide. Vision deficits in glaucoma result from the selective loss of retinal ganglion cells (RGC). Glial cell-mediated neuroinflammation has been proposed to contribute to disease pathophysiology, but whether this response is harmful or beneficial for RGC survival is not well understood. To test this, we characterized the role of ibudilast, a clinically approved cAMP phosphodiesterase (PDE) inhibitor with preferential affinity for PDE type 4 (PDE4). Here, we demonstrate that intraocular administration of ibudilast dampened macroglia and microglia reactivity in the retina and optic nerve hence decreasing production of proinflammatory cytokines in a rat model of ocular hypertension. Importantly, ibudilast promoted robust RGC soma survival, prevented axonal degeneration, and improved anterograde axonal transport in glaucomatous eyes without altering intraocular pressure. Intriguingly, ocular hypertension triggered upregulation of PDE4 subtype A in Müller glia, and ibudilast stimulated cAMP accumulation in these cells. Co-administration of ibudilast with Rp-cAMPS, a cell-permeable and non-hydrolysable cAMP analog that inhibits protein kinase A (PKA), completely blocked ibudilast-induced neuroprotection. Collectively, these data demonstrate that ibudilast, a safe and well-tolerated glial cell modulator, attenuates gliosis, decreases levels of proinflammatory mediators, and enhances neuronal viability in glaucoma through activation of the cAMP/PKA pathway. This study provides insight into PDE4 signaling as a potential target to counter the harmful effects associated with chronic gliosis and neuroinflammation in glaucoma.
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- 2016
- Full Text
- View/download PDF
6. Autophagy disruption reduces mTORC1 activation leading to retinal ganglion cell neurodegeneration associated with glaucoma
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Kang-Chieh Huang, Cátia Gomes, Yukihiro Shiga, Nicolas Belforte, Kirstin B. VanderWall, Sailee S. Lavekar, Clarisse M. Fligor, Jade Harkin, Adriana Di Polo, and Jason S. Meyer
- Abstract
Autophagy dysfunction has been associated with several neurodegenerative diseases including glaucoma, characterized by the degeneration of retinal ganglion cells (RGCs). However, the mechanisms by which autophagy dysfunction promotes RGC damage remain unclear. Here, we hypothesized that perturbation of the autophagy pathway results in increased autophagic demand, thereby downregulating signaling through mammalian target of rapamycin complex 1 (mTORC1), a negative regulator of autophagy, contributing to the degeneration of RGCs. We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor adenosine monophosphate-activated protein kinase (AMPK), along with subsequent neurodegeneration in RGCs differentiated from human pluripotent stem cells (hPSCs) with a glaucoma-associated variant of Optineurin (OPTN-E50K). Similarly, the microbead occlusion model of glaucoma resulting in ocular hypertension also exhibited autophagy disruption and mTORC1 downregulation. Pharmacological inhibition of mTORC1 in hPSC-derived RGCs recapitulated disease-related neurodegenerative phenotypes in otherwise healthy RGCs, while the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN-E50K RGCs. Taken together, these results highlight an important balance between autophagy and mTORC1 signaling essential for RGC homeostasis, while disruption to these pathways contributes to neurodegenerative features in glaucoma, providing a potential therapeutic target to prevent neurodegeneration.
- Published
- 2023
7. Pericyte dysfunction and loss of interpericyte tunneling nanotubes promote neurovascular deficits in glaucoma
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Luis Alarcon-Martinez, Yukihiro Shiga, Deborah Villafranca-Baughman, Nicolas Belforte, Heberto Quintero, Florence Dotigny, Jorge L. Cueva Vargas, and Adriana Di Polo
- Subjects
Male ,Nanotubes ,Multidisciplinary ,Magnetic Phenomena ,Retinal Vessels ,Glaucoma ,Cell Membrane Structures ,Microspheres ,Retina ,Tissue Culture Techniques ,Mice ,Gene Expression Regulation ,Animals ,Calcium ,Female ,Proteoglycans ,Antigens ,Pericytes ,Promoter Regions, Genetic ,Gene Deletion - Abstract
Significance The current lack of understanding of the mechanisms leading to neurovascular deficits in glaucoma is a major knowledge gap in the field. Retinal pericytes regulate microcirculatory blood flow and coordinate neurovascular coupling through interpericyte tunneling nanotubes (IP-TNTs). We demonstrate that pericytes constrict capillaries in a calcium-dependent manner during glaucomatous stress, decreasing blood supply and compromising neuronal function. Moreover, ocular hypertension damages IP-TNTs and impairs light-evoked neurovascular responses. The reestablishment of calcium homeostasis in pericytes restores vascular and neuronal function, and prevents retinal ganglion cell death in glaucomatous eyes. This study provides important insights into the therapeutic potential of pericytes to counter vascular dysregulation in glaucoma.
- Published
- 2022
8. Restoration of mitochondria axonal transport by adaptor Disc1 supplementation prevents neurodegeneration and rescues visual function
- Author
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Heberto Quintero, Yukihiro Shiga, Nicolas Belforte, Luis Alarcon-Martinez, Sana El Hajji, Deborah Villafranca-Baughman, Florence Dotigny, and Adriana Di Polo
- Subjects
Adenosine Triphosphate ,Dietary Supplements ,Nerve Tissue Proteins ,Axonal Transport ,General Biochemistry, Genetics and Molecular Biology ,Mitochondria - Abstract
Deficits in mitochondrial transport are a common feature of neurodegenerative diseases. We investigated whether loss of components of the mitochondrial transport machinery impinge directly on metabolic stress, neuronal death, and circuit dysfunction. Using multiphoton microscope live imaging, we showed that ocular hypertension, a major risk factor in glaucoma, disrupts mitochondria anterograde axonal transport leading to energy decline in vulnerable neurons. Gene- and protein-expression analysis revealed loss of the adaptor disrupted in schizophrenia 1 (Disc1) in retinal neurons subjected to high intraocular pressure. Disc1 gene delivery was sufficient to rescue anterograde transport and replenish axonal mitochondria. A genetically encoded ATP sensor combined with longitudinal live imaging showed that Disc1 supplementation increased ATP production in stressed neurons. Disc1 gene therapy promotes neuronal survival, reverses abnormal single-cell calcium dynamics, and restores visual responses. Our study demonstrates that enhancing anterograde mitochondrial transport is an effective strategy to alleviate metabolic stress and neurodegeneration.
- Published
- 2022
9. AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma
- Author
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Deborah Villafranca-Baughman, Adriana Di Polo, Jorge L. Cueva Vargas, Luis Alarcon-Martinez, Nicolas Belforte, Jessica Agostinone, and Florence Dotigny
- Subjects
0301 basic medicine ,Retinal Ganglion Cells ,genetic structures ,mTORC1 ,Biology ,Neurotransmission ,Mechanistic Target of Rapamycin Complex 1 ,Energy homeostasis ,Synapse ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,medicine ,Animals ,Humans ,Neurodegeneration ,RC346-429 ,Molecular Biology ,Metabolic stress ,Adenosine monophosphate-activated protein kinase ,Mammalian target of rapamycin ,Adenylate Kinase ,RC952-954.6 ,AMPK ,Glaucoma ,Dendrites ,medicine.disease ,eye diseases ,Enzyme Activation ,030104 developmental biology ,medicine.anatomical_structure ,Retinal ganglion cell ,Geriatrics ,Synapses ,Synapse disassembly ,Neurology. Diseases of the nervous system ,Neurology (clinical) ,sense organs ,Neuroscience ,030217 neurology & neurosurgery ,Glaucoma, Open-Angle ,Research Article - Abstract
Background The maintenance of complex dendritic arbors and synaptic transmission are processes that require a substantial amount of energy. Bioenergetic decline is a prominent feature of chronic neurodegenerative diseases, yet the signaling mechanisms that link energy stress with neuronal dysfunction are poorly understood. Recent work has implicated energy deficits in glaucoma, and retinal ganglion cell (RGC) dendritic pathology and synapse disassembly are key features of ocular hypertension damage. Results We show that adenosine monophosphate-activated protein kinase (AMPK), a conserved energy biosensor, is strongly activated in RGC from mice with ocular hypertension and patients with primary open angle glaucoma. Our data demonstrate that AMPK triggers RGC dendrite retraction and synapse elimination. We show that the harmful effect of AMPK is exerted through inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Attenuation of AMPK activity restores mTORC1 function and rescues dendrites and synaptic contacts. Strikingly, AMPK depletion promotes recovery of light-evoked retinal responses, improves axonal transport, and extends RGC survival. Conclusions This study identifies AMPK as a critical nexus between bioenergetic decline and RGC dysfunction during pressure-induced stress, and highlights the importance of targeting energy homeostasis in glaucoma and other neurodegenerative diseases.
- Published
- 2021
10. Visualization, Quantification, and Mapping of Immune Cell Populations in the Tumor Microenvironment
- Author
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Liliane Meunier, Geneviève Soucy, Simon Turcotte, Naglaa H. Shoukry, Thomas Fabre, Aurélie Cleret-Buhot, Manuel Flores Molina, Nicolas Belforte, and Mohamed N Abdelnabi
- Subjects
Hot Temperature ,Tissue Fixation ,Response to therapy ,Computer science ,Antibodies, Neoplasm ,General Chemical Engineering ,Cell ,Image processing ,Computational biology ,General Biochemistry, Genetics and Molecular Biology ,Automation ,Immune system ,Antigen ,Antigens, Neoplasm ,medicine ,Image Processing, Computer-Assisted ,Leukocytes ,Tumor Microenvironment ,Humans ,Tumor microenvironment ,Paraffin Embedding ,General Immunology and Microbiology ,Staining and Labeling ,General Neuroscience ,Visualization ,medicine.anatomical_structure ,Serial imaging ,Stromal Cells - Abstract
The immune landscape of the tumor microenvironment (TME) is a determining factor in cancer progression and response to therapy. Specifically, the density and the location of immune cells in the TME have important diagnostic and prognostic values. Multiomic profiling of the TME has exponentially increased our understanding of the numerous cellular and molecular networks regulating tumor initiation and progression. However, these techniques do not provide information about the spatial organization of cells or cell-cell interactions. Affordable, accessible, and easy to execute multiplexing techniques that allow spatial resolution of immune cells in tissue sections are needed to complement single cell-based high-throughput technologies. Here, we describe a strategy that integrates serial imaging, sequential labeling, and image alignment to generate virtual multiparameter slides of whole tissue sections. Virtual slides are subsequently analyzed in an automated fashion using user-defined protocols that enable identification, quantification, and mapping of cell populations of interest. The image analysis is done, in this case using the analysis modules Tissuealign, Author, and HISTOmap. We present an example where we applied this strategy successfully to one clinical specimen, maximizing the information that can be obtained from limited tissue samples and providing an unbiased view of the TME in the entire tissue section.
- Published
- 2020
11. Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease
- Author
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Adriana Di Polo, Heberto Quintero, Laurie Destroismaisons, Fany Panayi, Nicolas Belforte, Florence Dotigny, Caroline Louis, Christine Vande Velde, Luis Alarcon-Martinez, and Marius Chiasseu
- Subjects
Retinal Ganglion Cells ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,genetic structures ,Tau protein ,Mice, Transgenic ,tau Proteins ,lcsh:Geriatrics ,Biology ,Axonal Transport ,Retinal ganglion ,lcsh:RC346-429 ,Retina ,Amyloid beta-Protein Precursor ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Alzheimer Disease ,medicine ,Animals ,Retinal ganglion cell ,Neurodegeneration ,Molecular Biology ,lcsh:Neurology. Diseases of the nervous system ,medicine.disease ,eye diseases ,Anterograde axonal transport ,lcsh:RC952-954.6 ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Tauopathies ,Axoplasmic transport ,biology.protein ,sense organs ,Neurology (clinical) ,Tau ,Alzheimer's disease ,Alzheimer’s disease ,Neuroscience ,030217 neurology & neurosurgery ,Research Article - Abstract
Background Tau is an axon-enriched protein that binds to and stabilizes microtubules, and hence plays a crucial role in neuronal function. In Alzheimer’s disease (AD), pathological tau accumulation correlates with cognitive decline. Substantial visual deficits are found in individuals affected by AD including a preferential loss of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. At present, however, the mechanisms that underlie vision changes in these patients are poorly understood. Here, we asked whether tau plays a role in early retinal pathology and neuronal dysfunction in AD. Methods Alterations in tau protein and gene expression, phosphorylation, and localization were investigated by western blots, qPCR, and immunohistochemistry in the retina and visual pathways of triple transgenic mice (3xTg) harboring mutations in the genes encoding presenilin 1 (PS1M146 V), amyloid precursor protein (APPSwe), and tau (MAPTP301L). Anterograde axonal transport was assessed by intraocular injection of the cholera toxin beta subunit followed by quantification of tracer accumulation in the contralateral superior colliculus. RGC survival was analyzed on whole-mounted retinas using cell-specific markers. Reduction of tau expression was achieved following intravitreal injection of targeted siRNA. Results Our data demonstrate an age-related increase in endogenous retinal tau characterized by epitope-specific hypo- and hyper-phosphorylation in 3xTg mice. Retinal tau accumulation was observed as early as three months of age, prior to the reported onset of behavioral deficits, and preceded tau aggregation in the brain. Intriguingly, tau build up occurred in RGC soma and dendrites, while tau in RGC axons in the optic nerve was depleted. Tau phosphorylation changes and missorting correlated with substantial defects in anterograde axonal transport that preceded RGC death. Importantly, targeted siRNA-mediated knockdown of endogenous tau improved anterograde transport along RGC axons. Conclusions Our study reveals profound tau pathology in the visual system leading to early retinal neuron damage in a mouse model of AD. Importantly, we show that tau accumulation promotes anterograde axonal transport impairment in vivo, and identify this response as an early feature of neuronal dysfunction that precedes cell death in the AD retina. These findings provide the first proof-of-concept that a global strategy to reduce tau accumulation is beneficial to improve axonal transport and mitigate functional deficits in AD and tauopathies.
- Published
- 2017
12. A Magnetic Microbead Occlusion Model to Induce Ocular Hypertension-Dependent Glaucoma in Mice
- Author
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Jorge L. Cueva Vargas, Nicolas Belforte, Adriana Di Polo, and Yoko Ito
- Subjects
0301 basic medicine ,Intraocular pressure ,medicine.medical_specialty ,genetic structures ,General Chemical Engineering ,Glaucoma ,Ocular hypertension ,Eye ,Retinal ganglion ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Mice ,Ophthalmology ,Cornea ,Occlusion ,medicine ,Animals ,Humans ,Intraocular Pressure ,Axon Degeneration ,Neuronal Death ,Mouse Model ,General Immunology and Microbiology ,Aqueous humour ,business.industry ,Magnetic Phenomena ,General Neuroscience ,Optic Nerve ,Microbead (research) ,medicine.disease ,eye diseases ,Microspheres ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Medicine ,Ocular Hypertension ,sense organs ,Issue 109 ,business ,human activities ,Neuroscience - Abstract
The use of rodent models of glaucoma has been essential to understand the molecular mechanisms that underlie the pathophysiology of this multifactorial neurodegenerative disease. With the advent of numerous transgenic mouse lines, there is increasing interest in inducible murine models of ocular hypertension. Here, we present an occlusion model of glaucoma based on the injection of magnetic microbeads into the anterior chamber of the eye using a modified microneedle with a facetted bevel. The magnetic microbeads are attracted to the iridocorneal angle using a handheld magnet to block the drainage of aqueous humour from the anterior chamber. This disruption in aqueous dynamics results in a steady elevation of intraocular pressure, which subsequently leads to the loss of retinal ganglion cells, as observed in human glaucoma patients. The microbead occlusion model presented in this manuscript is simple compared to other inducible models of glaucoma and also highly effective and reproducible. Importantly, the modifications presented here minimize common issues that often arise in occlusion models. First, the use of a bevelled glass microneedle prevents backflow of microbeads and ensures that minimal damage occurs to the cornea during the injection, thus reducing injury-related effects. Second, the use of magnetic microbeads ensures the ability to attract most beads to the iridocorneal angle, effectively reducing the number of beads floating in the anterior chamber avoiding contact with other structures (e.g., iris, lens). Lastly, the use of a handheld magnet allows flexibility when handling the small mouse eye to efficiently direct the magnetic microbeads and ensure that there is little reflux of the microbeads from the eye when the microneedle is withdrawn. In summary, the microbead occlusion mouse model presented here is a powerful investigative tool to study neurodegenerative changes that occur during the onset and progression of glaucoma.
- Published
- 2016
13. AB011. Live imaging of retinal pericytes: evidence for early calcium uptake, capillary constriction and vascular dysregulation in ocular hypertension glaucoma
- Author
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Jorge L. Cueva Vargas, Nicolas Belforte, Deborah Villafranca-Baughman, Luis Alarcon-Martinez, and Adriana Di Polo
- Subjects
medicine.medical_specialty ,business.industry ,Glaucoma ,Ocular hypertension ,Retinal ,medicine.disease ,Calcium uptake ,Constriction ,Ophthalmology ,chemistry.chemical_compound ,chemistry ,Live cell imaging ,medicine ,business - Published
- 2018
14. AB015. Metabolic stress in glaucoma engages early activation of the energy biosensor adenosine monophosphate-activated protein kinase leading to neuronal dysfunction
- Author
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Jorge L. Cueva Vargas, Nicolas Belforte, and Adriana Di Polo
- Subjects
Adenosine monophosphate ,Ophthalmology ,chemistry.chemical_compound ,Chemistry ,medicine ,Glaucoma ,Metabolic Stress ,Early activation ,Protein kinase A ,medicine.disease ,Biosensor ,Cell biology - Published
- 2018
15. Therapeutic benefit of radial optic neurotomy in a rat model of glaucoma.
- Author
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Nicolás Belforte, Pablo H Sande, Nuria de Zavalía, Damián Dorfman, and Ruth E Rosenstein
- Subjects
Medicine ,Science - Abstract
Radial optic neurotomy (RON) has been proposed as a surgical treatment to alleviate the neurovascular compression and to improve the venous outflow in patients with central retinal vein occlusion. Glaucoma is characterized by specific visual field defects due to the loss of retinal ganglion cells and damage to the optic nerve head (ONH). One of the clinical hallmarks of glaucomatous neuropathy is the excavation of the ONH. The aim of this work was to analyze the effect of RON in an experimental model of glaucoma in rats induced by intracameral injections of chondroitin sulfate (CS). For this purpose, Wistar rats were bilaterally injected with vehicle or CS in the eye anterior chamber, once a week, for 10 weeks. At 3 or 6 weeks of a treatment with vehicle or CS, RON was performed by a single incision in the edge of the neuro-retinal ring at the nasal hemisphere of the optic disk in one eye, while the contralateral eye was submitted to a sham procedure. Electroretinograms (ERGs) were registered under scotopic conditions and visual evoked potentials (VEPs) were registered with skull-implanted electrodes. Retinal and optic nerve morphology was examined by optical microscopy. RON did not affect the ocular hypertension induced by CS. In eyes injected with CS, a significant decrease of retinal (ERG a- and b-wave amplitude) and visual pathway (VEP N2-P2 component amplitude) function was observed, whereas RON reduced these functional alterations in hypertensive eyes. Moreover, a significant loss of cells in the ganglion cell layer, and Thy-1-, NeuN- and Brn3a- positive cells was observed in eyes injected with CS, whereas RON significantly preserved these parameters. In addition, RON preserved the optic nerve structure in eyes with chronic ocular hypertension. These results indicate that RON reduces functional and histological alterations induced by experimental chronic ocular hypertension.
- Published
- 2012
- Full Text
- View/download PDF
16. Ischemic tolerance protects the rat retina from glaucomatous damage.
- Author
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Nicolás Belforte, Pablo H Sande, Nuria de Zavalía, Diego C Fernandez, Dafne M Silberman, Mónica S Chianelli, and Ruth E Rosenstein
- Subjects
Medicine ,Science - Abstract
Glaucoma is a leading cause of acquired blindness which may involve an ischemic-like insult to retinal ganglion cells and optic nerve head. We investigated the effect of a weekly application of brief ischemia pulses (ischemic conditioning) on the rat retinal damage induced by experimental glaucoma. Glaucoma was induced by weekly injections of chondroitin sulfate (CS) in the rat eye anterior chamber. Retinal ischemia was induced by increasing intraocular pressure to 120 mmHg for 5 min; this maneuver started after 6 weekly injections of vehicle or CS and was weekly repeated in one eye, while the contralateral eye was submitted to a sham procedure. Glaucoma was evaluated in terms of: i) intraocular pressure (IOP), ii) retinal function (electroretinogram (ERG)), iii) visual pathway function (visual evoked potentials, (VEPs)) iv) histology of the retina and optic nerve head. Retinal thiobarbituric acid substances levels were assessed as an index of lipid peroxidation. Ischemic conditioning significantly preserved ERG, VEPs, as well as retinal and optic nerve head structure from glaucomatous damage, without changes in IOP. Moreover, ischemia pulses abrogated the increase in lipid peroxidation induced by experimental glaucoma. These results indicate that induction of ischemic tolerance could constitute a fertile avenue for the development of new therapeutic strategies in glaucoma treatment.
- Published
- 2011
- Full Text
- View/download PDF
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