Assessment of retinal ganglion cell damage in glaucomatous optic neuropathy: Axon transport, injury and soma loss

Nuschke, Andrea C.; Farrell, Spencer; Levesque, Julie M.; Chauhan, Balwantray C.

doi:10.1016/j.exer.2015.06.006

Cited by 57 publications

(42 citation statements)

References 144 publications

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“…The gold standard is direct counting of the number of persistent axonal profiles in semithin nerve cross-sections (Nuschke et al, 2015), however for many labs this is not always feasible or practical. Alternatively, axon counts can be estimated by sampling nerve subareas, but this poses challenges since nerve degeneration can be highly variable across the nerve (Buckingham et al, 2008; Chauhan et al, 2006; Chen et al, 2011; Crish et al, 2010; Ebneter et al, 2010, 2012; Howell et al, 2007a; Howell et al, 2011; Inman et al, 2006; Isaacs et al, 2014; Jia et al, 2000; Joos et al, 2010; Mabuchi et al, 2003; Marina et al, 2010; May and Mittag, 2006; Reynaud et al, 2012; Sappington et al, 2010; Scholz et al, 2008; Teixeira et al, 2014; Templeton et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Early in DBA/2J glaucoma, sparse degenerative axonal profiles are interspersed within nerves with preserved axon densities, and as disease advances, there is progressive increase in axon degeneration and loss that culminates in axon depletion and nerve scarring (Crish et al, 2010; Inman et al, 2006; Libby et al, 2005a). Given the variable severity and progressive nature of glaucomatous optic nerve degeneration, the assessment of nerve damage in animal models of glaucoma is largely based on grading or quantifying the numbers of persistent axons (reviewed in Nuschke et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

“…Axon drop out can be diffuse and uniform across the entire nerve (Sappington et al, 2010), focal and heterogeneous between fascicles (Morrison et al, 1997), or a combination of both topographies, as in the DBA/2J model (Schlamp et al, 2006). Direct counting of the number of persistent axonal profiles in semithin nerve cross-sections is the standard and most accurate method to determine glaucomatous axon loss, and much effort continues to be devoted to perfecting this analysis (Nuschke et al, 2015). In rodent models of glaucoma, actual axon counts in light micrographs are performed manually or by semiautomated analysis in nerve subareas distributed in a fixed patterned or within zones selected for their uniform damage (Buckingham et al, 2008; Chauhan et al, 2006; Chen et al, 2011; Crish et al, 2010; Ebneter et al, 2010, 2012; Howell et al, 2007a; Howell et al, 2011; Inman et al, 2006; Isaacs et al, 2014; Jia et al, 2000; Joos et al, 2010; Mabuchi et al, 2003; Marina et al, 2010; May and Mittag, 2006; Sappington et al, 2010; Scholz et al, 2008; Templeton et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Glial coverage in the optic nerve expands in proportion to optic axon loss in chronic mouse glaucoma

Bosco

Breen

Anderson

et al. 2016

Experimental Eye Research

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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 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glial coverage in the optic nerve expands in proportion to optic axon loss in chronic mouse glaucoma

Bosco

Breen

Anderson

et al. 2016

Experimental Eye Research

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“…This review aims to provide a discussion on the above techniques, their strengths and weaknesses and accurate quantitative comparisons between RGC counting and RGC functional assessments. For quantifying RGC axonal loss and dysfunction in their axonal transport properties, see recent review(Nuschke et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Evaluating retinal ganglion cell loss and dysfunction

Mead

Tomarev

2016

Experimental Eye Research

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Retinal ganglion cells (RGC) bear the sole responsibility of propagating visual stimuli to the brain. Their axons, which make up the optic nerve, project from the retina to the brain through the lamina cribrosa and in rodents, decussate almost entirely at the optic chiasm before synapsing at the superior colliculus. For many traumatic and degenerative ocular conditions, the dysfunction and/or loss of RGC is the primary determinant of visual loss and are the measurable endpoints in current research into experimental therapies. To actually measure these endpoints in rodent models, techniques must ascertain both the quantity of surviving RGC and their functional capacity. Quantification techniques include phenotypic markers of RGC, retrogradely transported fluorophores and morphological measurements of retinal thickness whereas functional assessments include electroretinography (flash and pattern) and visual evoked potential. The importance of the accuracy and reliability of these techniques cannot be understated, nor can the relationship between RGC death and dysfunction. The existence of up to 30 types of RGC complicates the measuring process, particularly as these may respond differently to disease and treatment. Since the above techniques may selectively identify and ignore particular subpopulations, their appropriateness as measures of RGC survival and function may be further limited. This review discusses the above techniques in the context of their subtype specificity.

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“…As a result, glaucoma is now classified within a group of chronic neurodegenerative conditions that collectively, are the leading cause of irreversible blindness worldwide (1)(2)(3)(4)(5)(6). As indicated by glaucoma epidemiological surveys, primary open-angle and angle-closure glaucoma occur in the majority of patients with glaucoma (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Role of nuclear factor (erythroid-derived 2)-like 2 in the age-resistant properties of the glaucoma trabecular meshwork

Cheng¹,

Liang²,

Qi³

2017

Experimental and Therapeutic Medicine

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Abstract. Glaucoma is a major cause of irreversible blindness. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates the expression of numerous antioxidants within cells and is therefore a focus of current ophthalmic research. To determine the roles of Nrf2 in mediating the glaucoma trabecular meshwork (GTM), the present study evaluated the levels of Nrf2 expression in GTM and human trabecular meshwork (HTM) cells by reverse-transcription-quantitative polymerase chain reaction and western blot analysis. It was principally observed that Nrf2 expression was downregulated in GTM cells. In addition, to determine the influence of Nrf2 on the apoptosis and proliferation of GTM and HTM cells, transfection assays and western blotting were performed to evaluate the expression of apoptosis-related proteins. The results of the current study indicated that Nrf2 may promote viability and reduce apoptosis in GTM and HTM cells. Collectively, these data suggest that Nrf2 may be a novel therapeutic target to treat glaucoma.

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Assessment of retinal ganglion cell damage in glaucomatous optic neuropathy: Axon transport, injury and soma loss

Cited by 57 publications

References 144 publications

Glial coverage in the optic nerve expands in proportion to optic axon loss in chronic mouse glaucoma

Glial coverage in the optic nerve expands in proportion to optic axon loss in chronic mouse glaucoma

Evaluating retinal ganglion cell loss and dysfunction

Role of nuclear factor (erythroid-derived 2)-like 2 in the age-resistant properties of the glaucoma trabecular meshwork

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