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Alterations in molecular pathways in the retina of early experimental glaucoma eyes.

ABSTRACT: Glaucoma is a multifactorial, neurodegenerative disease. The molecular mechanisms that underlie the pathophysiological changes in glaucomatous eyes, especially at the early stage of the disease, are poorly understood. Here, we report the findings from a quantitative proteomic analysis of retinas from experimental glaucoma (EG) eyes. An early stage of EG was modeled on unilateral eyes of five nonhuman primates (NHP) by laser treatment-induced elevation of intraocular pressure (IOP). Retinal proteins were extracted from individual EG eyes and their contralateral control eyes of the same animals, respectively, and analyzed by quantitative mass spectrometry (MS). As a result, a total, 475 retinal proteins were confidently identified and quantified. Results of bioinformatic analysis of proteins that showed an increase in the EG eyes suggested changes in apoptosis, DNA damage, immune response, cytoskeleton rearrangement and cell adhesion processes. Interestingly, hemoglobin subunit alpha (HBA) and Ras related C3 botulinum toxin substrate 1 (Rac1) were among the increased proteins. Results of molecular modeling of HBA- and Rac1-associated signaling network implicated the involvement of Mitogen-Activated Protein Kinase (MAPK) pathway in the EG, through which Rac1 may exert a regulatory role on HBA. This is the first observation of this potentially novel signaling network in the NHP retina and in EG. Results of Western blot analyses for Rac1, HBA and a selected MAPK pathway protein indicated synergistic changes in all three proteins in the EG eyes. Further, results of hierarchical cluster analysis of proteomes of control eyes revealed a clear age-proteome relationship, and such relationship appeared disrupted in the EG eyes. In conclusion, our results suggested an increased presence of a potentially novel signaling network at the early stage of glaucoma, and age might be one of the determinant factors in retinal proteomic characteristics under normal conditions.

SUBMITTER: Cao L

PROVIDER: S-EPMC4446388 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeTo evaluate optic nerve vascular density using swept source optical coherence tomography angiography (OCTA) in patients with early primary open angle glaucoma (POAG), pre-perimetric glaucoma and normal eyes.MethodsThis is a prospective, observational study including 56 eyes in total and divided into 3 groups; 20 eyes with mild POAG, 20 pre-perimetric glaucoma eyes, and 16 age-matched normal eyes as controls. The optic disc region was imaged by a 1050-nm-wavelength swept-source OCT system (DRI OCT Triton, TOPCON). Vessel density was assessed as the ratio of the area occupied by the vessels in 3 distinct regions: 1) within the optic nerve head; 2) in the 3 mm papillary region around the optic disc; and 3) in the peripapillary region, defined as a 700-μm-wide elliptical annulus around the disc. The potential associations between vessel density and structural, functional measures were analyzed.ResultsThere was a statistically significant difference for the peripapillary vessel density, optic nerve head vessel density, and papillary vessel density among all the groups (p<0.001). Control eyes showed a significant difference for all measured vessel densities compared to glaucomatous eyes (p values from 0.001 to 0.024). There was a statistically significant difference between control and pre-perimetric glaucoma eyes for peripapillary, optic nerve head and papillary vessel density values (p values from 0.001 to 0.007). The optic nerve head vessel density, superior and inferior papillary area vessel density (Pearson r = 0.512, 0.436, 0.523 respectively) were highly correlated with mean overall, superior and inferior RNFL thickness in POAG eyes (p = 0.04, p = 0.02 and p = 0.04 respectively). Multiple linear regression analysis of POAG group showed that optic nerve head vessel density in POAG group was more strongly linked to RNFL thickness than to any other variables.ConclusionsEyes with mild POAG could be differentiated from pre-perimetric glaucoma eyes, which also could be differentiated from normal eyes using OCTA-derived retinal vessel density measurements.

Project description:BackgroundGlaucomatous optic neuropathy, a leading cause of blindness, can progress despite control of intraocular pressure - currently the main risk factor and target for treatment. Glaucoma progression shares mechanisms with neurodegenerative disease, including microglia activation. In the present model of ocular hypertension (OHT), we have recently described morphological signs of retinal microglia activation and MHC-II upregulation in both the untreated contralateral eyes and OHT eyes. By using immunostaining, we sought to analyze and quantify additional signs of microglia activation and differences depending on the retinal layer.MethodsTwo groups of adult Swiss mice were used: age-matched control (naïve, n = 12), and lasered (n = 12). In the lasered animals, both OHT eyes and contralateral eyes were analyzed. Retinal whole-mounts were immunostained with antibodies against Iba-1, MHC-II, CD68, CD86, and Ym1. The Iba-1+ cell number in the plexiform layers (PL) and the photoreceptor outer segment (OS), Iba-1+ arbor area in the PL, and area of the retina occupied by Iba-1+ cells in the nerve fiber layer-ganglion cell layer (NFL-GCL) were quantified.ResultsThe main findings in contralateral eyes and OHT eyes were: i) ameboid microglia in the NFL-GCL and OS; ii) the retraction of processes in all retinal layers; iii) a higher level of branching in PL and in the OS; iv) soma displacement to the nearest cell layers in the PL and OS; v) the reorientation of processes in the OS; vi) MHC-II upregulation in all retinal layers; vii) increased CD68 immunostaining; and viii) CD86 immunolabeling in ameboid cells. In comparison with the control group, a significant increase in the microglial number in the PL, OS, and in the area occupied by Iba-1+ cells in the NFL-GCL, and significant reduction of the arbor area in the PL. In addition, rounded Iba-1+ CD86+ cells in the NFL-GCL, OS and Ym1+ cells, and rod-like microglia in the NFL-GCL were restricted to OHT eyes.ConclusionsSeveral quantitative and qualitative signs of microglia activation are detected both in the contralateral and OHT eyes. Such activation extended beyond the GCL, involving all retinal layers. Differences between the two eyes could help to elucidate glaucoma pathophysiology.

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Alterations in molecular pathways in the retina of early experimental glaucoma eyes.

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