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This review arose from a discussion of regenerative therapies to treat optic nerve degeneration in glaucoma at the 2015 Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration. In addition to the authors, participants included Jonathan Crowston, Andrew Huberman, Elaine Johnson, Richard Lu, Hemai Phatnami, Rebecca Sappington, and Don Zack. Glaucoma is a neurodegenerative disease of the optic nerve, and is the leading cause of irreversible blindness worldwide. The disease progresses as sensitivity to intraocular pressure (IOP) is conveyed through the optic nerve head to distal retinal ganglion cell (RGC) projections. Because the nerve and retina are components of the central nervous system (CNS), their intrinsic regenerative capacity is limited. However, recent research in regenerative therapies has resulted in multiple breakthroughs that may unlock the optic nerve's regenerative potential. Increasing levels of Schwann-cell derived trophic factors and reducing potent cell-intrinsic suppressors of regeneration have resulted in axonal regeneration even beyond the optic chiasm. Despite this success, many challenges remain. RGC axons must be able to form new connections with their appropriate targets in central brain regions and these connections must be retinotopically correct. Furthermore, for new axons penetrating the optic projection, oligodendrocyte glia must provide myelination. Additionally, reactive gliosis and inflammation that increase the regenerative capacity must be outweigh pro-apoptotic processes to create an environment within which maximal regeneration can occur.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Within the white matter, axonal loss by neurodegeneration is coupled to glial cell changes in gene expression, structure and function commonly termed gliosis. Recently, we described the highly variable expansion of gliosis firstname.lastname@example.org in degenerative optic nerves from the DBA/2J mouse model of chronic, age-related glaucoma. Here, to estimate and compare the levels of axonal loss with the expansion of glial coverage and axonal degeneration in DBA/2J nerves, we combined semiautomatic axon counts with threshold-based segmentation of total glial/scar areas and degenerative axonal profiles in plastic cross-sections. In nerves ranging from mild to severe degeneration, we found that the progression of axonal dropout is coupled to an increase of gliotic area. We detected a strong correlation between axon loss and the aggregate coverage by glial cells and scar, whereas axon loss did not correlate with the small fraction of degenerating profiles. Nerves with low to medium levels of axon loss displayed moderate glial reactivity, consisting of hypertrophic astrocytes, activated microglia and normal distribution of oligodendrocytes, with minimal reorganization of the tissue architecture. In contrast, nerves with extensive axonal loss showed prevalent rearrangement of the nerve, with loss of axon fascicle territories and enlarged or almost continuous gliotic and scar domains, containing reactive astrocytes, oligodendrocytes and activated microglia. These findings support the value of optic nerve gliotic expansion as a quantitative estimate of optic neuropathy that correlates with axon loss, applicable to grade the severity of optic nerve damage in mouse chronic glaucoma.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Glaucoma challenges the survival of retinal ganglion cell axons in the optic nerve through processes dependent on both aging and ocular pressure. Relevant stressors likely include complex interplay between axons and astrocytes, both in the retina and optic nerve. In the DBA/2J mouse model of pigmentary glaucoma, early progression involves axonopathy characterized by loss of functional transport prior to outright degeneration. Here we describe novel features of early pathogenesis in the DBA/2J nerve. With age the cross-sectional area of the nerve increases; this is associated generally with diminished axon packing density and survival and increased glial coverage of the nerve. However, for nerves with the highest axon density, as the nerve expands mean cross-sectional axon area enlarges as well. This early expansion was marked by disorganized axoplasm and accumulation of hyperphosphorylated neurofilamants indicative of axonopathy. Axon expansion occurs without loss up to a critical threshold for size (about 0.45-0.50 μm(2)), above which additional expansion tightly correlates with frank loss of axons. As well, early axon expansion prior to degeneration is concurrent with decreased astrocyte ramification with redistribution of processes towards the nerve edge. As axons expand beyond the critical threshold for loss, glial area resumes an even distribution from the center to edge of the nerve. We also found that early axon expansion is accompanied by reduced numbers of mitochondria per unit area in the nerve. Finally, our data indicate that both IOP and nerve expansion are associated with axon enlargement and reduced axon density for aged nerves. Collectively, our data support the hypothesis that diminished bioenergetic resources in conjunction with early nerve and glial remodeling could be a primary inducer of progression of axon pathology in glaucoma.
Copyright © 2015 Elsevier Ltd. All rights reserved.
How neurons respond to stress in degenerative disease is of fundamental importance for identifying mechanisms of progression and new therapeutic targets. Members of the transient receptor potential (TRP) family of cation-selective ion channels are candidates for mediating stress signals, since different subunits transduce a variety of stimuli relevant in both normal and pathogenic physiology. We addressed this possibility for the TRP vanilloid-1 (TRPV1) subunit by comparing how the optic projection of Trpv1(-/-) mice and age-matched C57 controls responds to stress from elevated ocular pressure, the critical stressor in the most common optic neuropathy, glaucoma. Over a 5 week period of elevated pressure induced by microbead occlusion of ocular fluid, Trpv1(-/-) accelerated both degradation of axonal transport from retinal ganglion cells to the superior colliculus and degeneration of the axons themselves in the optic nerve. Ganglion cell body loss, which is normally later in progression, occurred in nasal sectors of Trpv1(-/-) but not C57 retina. Pharmacological antagonism of TRPV1 in rats similarly accelerated ganglion cell axonopathy. Elevated ocular pressure resulted in differences in spontaneous firing rate and action potential threshold current in Trpv1(-/-) ganglion cells compared with C57. In the absence of elevated pressure, ganglion cells in the two strains had similar firing patterns. Based on these data, we propose that TRPV1 may help neurons respond to disease-relevant stressors by enhancing activity necessary for axonal signaling.
The purpose of this study was to investigate if neuroprotective drugs can cross the optic nerve sheath in vitro. Four optic nerves were used for this study. Two porcine nerves were harvested at the time of euthanasia and two human nerves were obtained at the time of therapeutic globe enucleation. The optic nerve sheaths were dissected and placed as a membrane in a two chamber diffusion cell to test meningeal penetration by both brimonidine alone and brimonidine encapsulated in nanoparticle (NP-brimonidine). Brimonidine concentration was assayed by UV-vis spectrometer measurement of absorbance at 389 nm. Increasing concentration of brimonidine on the receiver side of the chamber was measured in both the brimonidine alone and the brimonidine encapsulated experiments. The human data were fitted with a two parameter exponential regression analysis (brimonidine alone donor r(2) = 0.87 and receiver r(2) = 0.80, NP-brimonidine donor r(2) = 0.79 and receiver r(2) = 0.84). Time constant (τ) was 10.2 h (donor) and 13.1 h (receiver) in the brimonidine study, and 24.0 h (donor) and 15.9 h (receiver) in the NP-brimonidine study. Encapsulated brimonidine had a longer time to reach equilibrium. Passage of brimonidine through the optic nerve sheath was demonstrated in the experiments. Increase in time constants when comparing the NP-brimonidine with the brimonidine curves in the human studiesindicates that diffusion is delayed by the initial parameter of drug being loaded in NP. Direct treatment of injured optic nerve axons may be possible by trans-meningeal drug diffusion.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Failure of anterograde transport to distal targets in the brain is a common feature of neurodegenerative diseases. We have demonstrated in rodent models of glaucoma, the most common optic neuropathy, early loss of anterograde transport along the retinal ganglion cell (RGC) projection to the superior colliculus (SC) is retinotopic and followed by a period of persistence of RGC axon terminals and synapses through unknown molecular pathways. Here we use the DBA/2J mouse model of hereditary glaucoma and an acute rat model to demonstrate that retinotopically focal transport deficits in the SC are accompanied by a spatially coincident increase in brain-derived neurotrophic factor (BDNF), especially in hypertrophic astrocytes. These neurochemical changes occur prior to loss of RGC synapses in the DBA/2J SC. In contrast to BDNF protein, levels of Bdnf mRNA decreased with transport failure, even as mRNA encoding synaptic structures remained unchanged. In situ hybridization signal for Bdnf mRNA was the strongest in SC neurons, and labeling for the immature precursor pro-BDNF was very limited. Subcellular fractionation of SC indicated that membrane-bound BDNF decreased with age in the DBA/2J, while BDNF released from vesicles remained high. These results suggest that in response to diminished axonal function, activated astrocytes in the brain may sequester mature BDNF released from target neurons to counter stressors that otherwise would challenge survival of projection synapses.
Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.
Glaucoma is a common optic neuropathy with a complex etiology often linked to sensitivity to intraocular pressure. Though the precise mechanisms that mediate or transduce this sensitivity are not clear, the axon of the retinal ganglion cell appears to be vulnerable to disease-relevant stressors early in progression. One reason may be because the axon is generally thin for both its unmyelinated and myelinated segment and much longer than the thicker unmyelinated axons of other excitatory retinal neurons. This difference may predispose the axon to metabolic and oxidative injury, especially at distal sites where pre-synaptic terminals form connections in the brain. This idea is consistent with observations of early loss of anterograde transport at central targets and other signs of distal axonopathy that accompany physiological indicators of progression. Outright degeneration of the optic projection ensues after a critical period and, at least in animal models, is highly sensitive to cumulative exposure to elevated pressure in the eye. Stress emanating from the optic nerve head can induce not only distal axonopathy with aspects of dying back neuropathy, but also Wallerian degeneration of the optic nerve and tract and a proximal program involving synaptic and dendritic pruning in the retina. Balance between progressive and acute mechanisms likely varies with the level of stress placed on the unmyelinated axon as it traverses the nerve head, with more acute insult pushing the system toward quicker disassembly. A constellation of signaling factors likely contribute to the transduction of stress to the axon, so that degenerative events along the length of the optic projection progress in retinotopic fashion. This pattern leads to well-defined sectors of functional depletion, even at distal-most sites in the pathway. While ganglion cell somatic drop-out is later in progression, some evidence suggests that synaptic and dendritic pruning in the retina may be a more dynamic process. Structural persistence both in the retina and in central projection sites offers the possibility that intrinsic self-repair pathways counter pathogenic mechanisms to delay as long as possible outright loss of tissue.
Copyright © 2012 Elsevier Ltd. All rights reserved.
PURPOSE - To characterize a glaucoma model of mice, the authors adopted and modified a method of inducing the chronic elevation of intraocular pressure (IOP) by anterior chamber injection of polystyrene microbeads.
METHODS - Chronic elevation of IOP was induced unilaterally in adult C57BL/6J mice by injecting polystyrene microbeads to the anterior chamber. Effectiveness of microbeads of different sizes (small, 10 μm; large, 15 μm) on inducing IOP elevation was compared, and IOP was measured every other day using a tonometer. After maintaining elevated IOP for 2, 4, or 8 weeks, the degree of RGC and axon degeneration was assessed quantitatively using electron microscopy, fluorogold, retrograde labeling, and immunohistochemistry.
RESULTS - Eighty-one of 87 mice that received anterior chamber injection of microbeads exhibited consistent IOP elevation above that of control eyes. Injection of small microbeads induced longer and higher peak value of IOP elevation compared with that of the large microbeads. A single injection of small microbeads resulted in a 4-week elevation of IOP that was maintained to an 8-week period after a second injection of microbeads in week 4. As the duration of IOP elevation increased, RGC bodies and their axons degenerated progressively and reached an approximately 50% loss after an 8-week elevation of IOP.
CONCLUSIONS - Anterior chamber injection of microbeads effectively induced IOP elevation and glaucomatous optic neuropathy in mice. Development of an inducible mouse model of elevated IOP will allow applications of mouse genetic technology to the investigation of the mechanisms and the evaluation of treatment strategies of glaucoma.
PURPOSE - Intraocular pressure (IOP) fluctuations may occur in patients with glaucoma, but how these fluctuations affect axonal populations in the optic nerve and other structures in the eye has been difficult to assess. This study developed a rat model to evaluate the effect of intermittent controlled elevations in IOP on the morphology of the rat optic nerve.
METHODS - IOP was transiently elevated for 1 hour on each of 6 days a week over 6 weeks with an adjustable vascular loop around the right topically anesthetized eye of Sprague-Dawley rats. IOP was measured by pneumatonometer before, immediately after, and at the end of 1 hour of treatment with ligature. Globes and optic nerve segments were prepared for histology and morphometry.
RESULTS - Mean baseline IOP of 14.9 ± 1.8 mm Hg increased to 35.3 ± 2.6 mm Hg (P < 0.001) during 1-hour treatments and returned to 15.0 ± 2.2 mm Hg (P = 0.84) 1 hour after completion. The contralateral untreated eyes had a mean IOP of 14.2 ± 1.9 mm Hg at baseline and 14.6 ± 1.9 mm Hg at the end of treatment. Nerve fiber layer thinning (22%-25%) corresponded with a decrease (7%-10%) in soma number in the ganglion cell layer. Optic nerves displayed axonal degeneration with a modest axon loss of 6% and increased expression of glial acidic fibrillary protein in astrocytes.
CONCLUSIONS - Controlled daily 1-hour IOP elevations can be performed with an adjustable vascular loop in rats. After only 6 weeks, intermittent elevations in IOP produce changes in optic nerve consistent with early degeneration reported in chronic models of glaucoma.
PURPOSE - To test the hypothesis that immune activation occurs in glaucoma by comparing concentrations of multiple cytokines in aqueous humor (AH) from patients with primary open angle glaucoma (POAG) and from cataract patients without glaucoma as controls.
METHODS - Cytokine concentrations in AH obtained during surgery were measured using microparticle-based immunoassays. Localized expression of IL-8 protein was investigated by immunohistochemistry of human eyes.
RESULTS - Eight cytokines (IL-1β, IL-2, IL-4, IL-5, IL-10, IL-12, IFN-γ, and TNF-α) were below the limits of detection, and two cytokines (IL-18 and IL-15) were detected at low levels or in only a few patients. Although IL-6 was detected in 26 of 30 control patients (median, 2.7 pg/mL) and in 23 of 29 POAG patients (median, 1.6 pg/mL), the difference was not statistically significant. IL-8 was detected in 28 of 30 control patients (median, 1.8 pg/mL) and in all 29 POAG patients (median, 4.9 pg/mL). The higher IL-8 concentration in the AH of POAG patients was statistically significant (P < 0.001). In pairs of eyes from patients with asymmetric glaucomatous optic nerve damage, IL-8 concentration was higher in the AH of the more severely affected eye (P < 0.05). Patients with severe visual field defects had higher IL-8 concentrations in the AH than did patients with mild visual field defects. IL-8 protein expression was found in human retina and optic nerve.
CONCLUSIONS - Concentration of the inflammatory cytokine IL-8 is significantly elevated in the AH of POAG patients, supporting the hypothesis that immune activation occurs in glaucoma.