Retinal microglia induce MGnD molecular signature in the DBA/2J glaucoma model
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE192505 | GEO | 2022/08/16
REPOSITORIES: GEO
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Project description:The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer’s disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here we find that in two mouse glaucoma models and in human glaucomatous retinas, microglia transition to a neurodegenerative (MGnD) phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3). Mice in which Apoe was targeted in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss despite elevated intraocular pressure (IOP). Similar to Apoe–/– retinal microglia, APOE4 microglia did not upregulate MGnD genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma, and that the APOE-Galectin-3 signaling pathway can be targeted to treat this blinding disease.
2022-08-16 | GSE192509 | GEO
Project description:The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer’s disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here we find that in two mouse glaucoma models and in human glaucomatous retinas, microglia transition to a neurodegenerative (MGnD) phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3). Mice in which Apoe was targeted in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss despite elevated intraocular pressure (IOP). Similar to Apoe–/– retinal microglia, APOE4 microglia did not upregulate MGnD genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma, and that the APOE-Galectin-3 signaling pathway can be targeted to treat this blinding disease.
2022-08-16 | GSE192508 | GEO
Project description:The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer’s disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here we find that in two mouse glaucoma models and in human glaucomatous retinas, microglia transition to a neurodegenerative (MGnD) phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3). Mice in which Apoe was targeted in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss despite elevated intraocular pressure (IOP). Similar to Apoe–/– retinal microglia, APOE4 microglia did not upregulate MGnD genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma, and that the APOE-Galectin-3 signaling pathway can be targeted to treat this blinding disease.
2022-08-16 | GSE192507 | GEO
Project description:The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer’s disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here we find that in two mouse glaucoma models and in human glaucomatous retinas, microglia transition to a neurodegenerative (MGnD) phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3). Mice in which Apoe was targeted in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss despite elevated intraocular pressure (IOP). Similar to Apoe–/– retinal microglia, APOE4 microglia did not upregulate MGnD genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma, and that the APOE-Galectin-3 signaling pathway can be targeted to treat this blinding disease.
2022-08-16 | GSE192506 | GEO
Project description:Goals of the study: 1. Assess the gene expression profile in rat RGC after experimental IOP elevation to elucidate the molecular mechanisms of RGC death. 2. Identify potentially novel genes and pathways that may contribute to RGC death in glaucoma. Background: Glaucoma is a neurodegenerative disease characterized by the slow, progressive degeneration of RGC. Elevated IOP is the biggest risk factor for developing glaucoma, loss of RGC and optic nerve atrophy. The pathophysiology of glaucomatous neurodegeneration is not fully understood. It is now clear that RGC die by apoptosis in glaucoma. However, what triggers the apoptosis is still unknown. So far, several gene expression studies have been performed on the retina as a whole. These studies revealed up and downregulation of many genes in response to elevated IOP and optic nerve transection. However, the retina is a complex tissue composed of neuronal, glial and vascular cell types. The RGCs only comprise 5% or less of retinal cells. The gene expression profiles from whole retina can not represent of RGC gene expression. In the current study, we sought to investigate the whole genome regulation of the RGCs in glaucoma. The study was carried out in 3 adult male Brown Norway rats with experimental glaucoma. An equal number of RGCs were captured from normal eyes and eyes with elevated IOP. Gene expression in the glaucomatous RGC was compared with that in the fellow RGC by using Affymetrix Gene chip.
2010-10-01 | E-GEOD-12596 | biostudies-arrayexpress
Project description:Goals of the study: 1. Assess the gene expression profile in rat RGC after experimental IOP elevation to elucidate the molecular mechanisms of RGC death. 2. Identify potentially novel genes and pathways that may contribute to RGC death in glaucoma. Background: Glaucoma is a neurodegenerative disease characterized by the slow, progressive degeneration of RGC. Elevated IOP is the biggest risk factor for developing glaucoma, loss of RGC and optic nerve atrophy. The pathophysiology of glaucomatous neurodegeneration is not fully understood. It is now clear that RGC die by apoptosis in glaucoma. However, what triggers the apoptosis is still unknown. So far, several gene expression studies have been performed on the retina as a whole. These studies revealed up and downregulation of many genes in response to elevated IOP and optic nerve transection. However, the retina is a complex tissue composed of neuronal, glial and vascular cell types. The RGCs only comprise 5% or less of retinal cells. The gene expression profiles from whole retina can not represent of RGC gene expression. In the current study, we sought to investigate the whole genome regulation of the RGCs in glaucoma.
2010-10-01 | GSE12596 | GEO
Project description:Elevated intraocular pressure (IOP) is the major risk factor for glaucoma, a sight threatening disease of retinal ganglion cells (RGCs) and their axons. Despite the central importance of IOP, details of the impact of IOP elevation on RGC gene expression remain elusive. We developed a novel 4-step immunopanning protocol to extract adult mouse RGCs with high fidelity and used it to isolate RGCs from wild type mice exposed to 2 weeks of IOP elevation generated by the microbead model. IOP was elevated to 2 distinct levels which were defined as Mild (IOP increase >1mmHg and <4mmHg) and Moderate (IOP increase > 4mmHg). RNA sequencing was used to compare the transcriptional environment at each IOP level. Differentially expressed genes were markedly different between the 2 groups, and pathway analysis revealed frequently opposed responses between the IOP levels. These results suggest that the magnitude of IOP elevation has a critical impact on RGC transcriptional changes. Furthermore, it is possible that an IOP-based set point exists within RGCs to impact the direction of transcriptional change. It is possible that this improved understanding of changes in RGC gene expression can ultimately lead to novel diagnostics and therapeutics for glaucoma.
2019-02-22 | GSE122205 | GEO
Project description:Glaucoma is not only the second leading cause of blindness worldwide, but patient numbers will also increase significantly in the coming years due to aging societies. Glaucoma is a progressive optic neuropathy with changes at the optic nerve head, gradual retinal ganglion cell (RGC) death, and visual field loss [1]. Unfortunately, glaucoma can remain asymptomatic until it is rather far progressed, hence about 10-50 % of patients are unaware they suffer from this disease. High intraocular pressure (IOP) is the main risk factor; however, normal-tension glaucoma (NTG) occurs in patients with physiological IOP [2]. This form account for about 30 % of glaucoma patients [3]. Furthermore, sustained IOP lowering can slow down, but does not completely stop disease progression in patients. [4, 5]. Additionally, the administration of topical glaucoma medications can lead to side effects, such as ocular irritation, decreasing the compliance of patients. These facts emphasize the importance of discovering new treatment strategies. The exact pathogenesis for glaucoma is still unknown, but several factors are considered to be involved (fig.1). The most prominent factor is an elevated IOP, which can cause blockade of axonal protein transport at the lamina cribrosa, causing an initial axonal damage and RGC death by trophic insufficiency. In addition, ischemic/hypoxic damage [6], astrocyte and glia cell alterations, and excessive stimulation of the glutamatergic system [7] are discussed as possible pathomechanisms. Moreover, an involvement of the immune system is considered [8-10]. In glaucoma patients, up- and downregulations in the systemic and ocular antibody profile were detected [11-13]. Also, antibody deposits were observed in glaucomatous retinae [14]. It is likely that a combination of several pathogenic factors/mechanisms increases the possibility of developing glaucoma. For the investigation of pathomechanisms and novel therapies, it is necessary to have suitable models that allow such screening. To investigate whether antibodies detected in glaucoma patients are part of glaucoma pathogenesis or a result of disease progression, the experimental autoimmune glaucoma (EAG) animal model was established. This animal model is based on the fact that autoantibodies against S100B, a small calcium binding protein expressed in glia cells, were found to be increased in glaucoma patients [15]. In this model, an immunization with S100B led to a significant loss of RGCs after 28 days and a fast degeneration of optic nerves [20]. The IOP in this model was not altered. Therefore, we were able to mimic the effects seen in NTG patients, an IOP-independent glaucomatous degeneration, by immunizing rats with S100B. S100B is a calcium-binding protein. In the central nervous system (CNS), it is mainly expressed by glial cells such as oligodendrocytes, Schwann cells, ependymal cells, retinal Müller cells and astrocytes [16]. S100B regulates and maintains the homeostasis of the important second messenger calcium and is therefore involved in many cell activities, such as signal transduction, cell differentiation, regulation of cell motility, transcription and cell cycle processes [17, 18]. Extracellularly, S100B can act as a signal molecule and bind receptors such as the receptor for advanced glycation end products (RAGE). In high concentrations, S100B can have negative effects and lead to cell death. For example, the binding of RAGE can induce the activation of microglia cells leading to a release of proinflammatory cytokines to an excessive extent [19]. Furthermore, there seems to be a link between S100B and neuronal diseases. In glaucoma patients, high antibody titers against S100B were found [20]. To investigate the effect of S100B in glaucoma more precisely, the immunization with S100B leads to a loss of retinal ganglion cells (RGCs) without an elevation of the IOP after 28 days in the EAG model [21, 22]. The goal of the present study was to detect the retinal biomarkers in EAG animals 7 and 14 days after immunization with S100B. To detect these new markers in disease development, a label free quantitative mass spectrometry-based approach will be used.
2022-02-16 | PXD023995 | Pride
Project description:Neuroinflammation is a crucial process for the loss of retinal ganglion cells (RGC), a major characteristic of glaucoma. High expression of high mobility group box protein 1 (HMGB1) plays a detrimental role in inflammatory processes and is elevated in the retinas of glaucoma patients. Therefore, this study aimed to investigate the effects of intravitreal injection of an anti-HMGB1 monoclonal antibody (anti-HMGB1 Ab) in an experimental animal model of glaucoma. Two groups of Spraque Dawley rats received episcleral vein occlusion to chronically elevate intraocular pressure (IOP): (1) IgG group, intravitreal injection of an unspecific IgG as a control, n=5, (2) HMGB1 group, intravitreal injection of an anti-HMGB1 Ab, n=6. IOP, retinal nerve fiber layer thickness (RNFLT), and the retinal flash response was monitored longitudinally. Post-mortem examinations included immunohistochemistry, microarray, and mass spectrometric analysis. RNFLT was significantly increased in the HMGB1 group compared to the IgG group (p<0.001). RGC density showed improved neuronal cell survival in the retina in HMGB1 compared to the IgG group (p<0.01). Mass spectrometric proteomic analysis of retinal tissue showed increased abundance of RNA metabolism-associated heterogeneous nuclear ribonucleoproteins (hnRNPs), such as hnRNP U, D, and H2, in animals injected with the anti-HMGB1 Ab, indicating that application of the antibody may cause increased gene expression. Microarray analysis showed significantly decreased expression of C-X-C motif chemokine ligand 8 (CXCL8, p<0.05) and connective tissue growth factor (CTGF, p<0.01) in the HMGB1 group. Thus, these data suggest that intravitreal injection of anti-HMGB1 Ab reduced HMGB1-dependent inflammatory signaling and mediated RGC neuroprotection.
2022-05-20 | PXD031987 | Pride
Project description:Microglia play a pivotal role in the maintenance of brain homeostasis, but lose their homeostatic function during the course of neurodegenerative disorders. We identified a specific APOE-dependent molecular signature in microglia isolated from mouse models of amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer’s disease (SOD1, EAE and APP-PS1) and in microglia surrounding neuritic A-plaques in human Alzheimer’s disease brain. This is mediated by a switch from a (M0)-homeostatic to (MGnD)-neurodegenerative phenotype following phagocytosis of apoptotic neurons via the TREM2-APOE pathway. TREM2 induces APOE signaling which is a negative regulator of the transcription program in M0-homeostatic microglia. Targeting the TREM2-APOE pathway restores the M0-homeostatic signature of microglia in APP-PS1 and SOD1 mice and prevents from neuronal loss in an acute model of neurodegeneration. In SOD1 mice, TREM2 regulates MGnD in a gender-dependent manner. APOE-mediated MGnD microglia lose their tolerogenic function. Taken together, our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target to restore homeostatic microglia.
2017-09-19 | GSE102564 | GEO