APOE4 retinal microglia remain homeostatic in glaucoma.
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ABSTRACT:
PROVIDER: PRJNA791674 | ENA |
REPOSITORIES: ENA
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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 | 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 | GSE192508 | GEO
Project description:Apoe–/– retinal microglia remain homeostatic despite elevated IOP in the microbead glaucoma model.
| PRJNA791673 | ENA
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 | GSE192505 | 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: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:Intraocular pressure was elevated through episkleral vein occlusion by thermic cauterization of SD rats. Animals were further sacrificed after different periods of elevated IOP and the retinal proteins were investigated for alterations regarding the relative protein level in this experimental model of glaucoma.
2017-04-11 | PXD005258 | Pride
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:Glaucoma is a multifactorial neurodegenerative disease characterized by the progressive and irreversible degeneration of the optic nerve and retinal ganglion cells. Despite medical advances aiming at slowing degeneration down, around 40% of treated glaucomatous patients will undergo vision loss. It is thus of utmost importance to have a better understanding of the disease and to investigate more deeply its early causes. The transcriptional coactivator YAP, an important regulator of eye homeostasis, has recently drawn attention in the glaucoma research field. Here we show that Yap conditional knockout mice (Yap cKO), in which the deletion of Yap is induced in both Müller glia (i.e. the only retinal YAP-expressing cells) and the non-pigmented epithelial cells of the ciliary body, exhibit a breakdown of the aqueous-blood barrier, accompanied by a progressive collapse of the ciliary body. A similar phenotype is observed in human samples that we obtained from patients presenting with uveitis. In addition, aged Yap cKO mice harbor glaucoma-like features, including deregulation of key homeostatic Müller-derived proteins, retinal vascular defects, optic nerve degeneration and retinal ganglion cell death. Finally, transcriptomic analysis of Yap cKO retinas pointed to early-deregulated genes involved in extracellular matrix organization potentially underlying the onset and/or progression of the observed phenotype. Together, our findings reveal the essential role of YAP in preserving the integrity of the ciliary body and retinal ganglion cells, thereby preventing the onset of uveitic glaucoma-like features.
2024-01-01 | GSE251685 | GEO