A biomechanical paradigm for axonal insult within the optic nerve head in aging and glaucoma

Burgoyne, Claude F.

doi:10.1016/j.exer.2010.09.005

Cited by 345 publications

(318 citation statements)

References 167 publications

(265 reference statements)

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“…glaucoma | astrocytes | complement | EGFR | WLDS G laucoma is a common disorder characterized by the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve (1)(2)(3). Intraocular pressure (IOP) elevation is a major risk factor for developing glaucoma (4).…”

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confidence: 99%

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Harder

Braine

Williams

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wld s allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wld s mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wld s mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/ 2J.Wld s mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.G laucoma is a common disorder characterized by the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve (1-3). Intraocular pressure (IOP) elevation is a major risk factor for developing glaucoma (4). Harmful IOP leads to changes in immune response pathways in nonneuronal cells, such as astrocytes and microglia/monocytes (5-9). Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12). In glaucoma, immune responses are known to occur at predegenerative stages (5, 8), but key questions remain unanswered (2, 13-15). It is not known whether the earliest immune responses are protective or damaging, or which events irreversibly damage the optic nerve. Moreover, it is not known whether the immune responses are secondary to RGC dysfunction or occur independently, possibly as a more direct result of IOP elevation.In glaucoma, an early insult to RGC axons occurs where they exit the eye in the optic nerve head (ONH) (16)(17)(18)(19)(20). Modeling shows that an increase in IOP inside the eye leads to increased strain in this critical region (21,22). To understand the molecular responses occurring during glaucoma, gene expression profiles of human lamina astrocytes and ONH tissue from animal models hav...

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mentioning

confidence: 99%

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Harder

Braine

Williams

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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“…The first and already classical paradigm is the biomechanic hypothesis [25,26], in which stress forces acting through the lamina cribrosa sclerae are transmitted to axons. Second historically but perhaps the most accepted is the ischemic hypothesis [27], in which the blood perfusion of the neural tissue is compromised.…”

Section: Current Paradigmsmentioning

confidence: 99%

Glaucoma as a Tax on Hominid Evolution. Constraints of the Experimental Animal Models of Glaucoma

Carreras¹

2016

J Clin Exp Ophthalmol

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Glaucoma continues to be a mysterious disease. High intraocular pressure (IOP), once the landmark of the disease, has been relegated to the humble role of risk factor, despite the fact that lowering IOP continues to be the only partially successful treatment. Even with an IOP successfully controlled to statistical standards, many patients still mysteriously continue to progressively lose neural tissue. A novel pathogenetical mechanism has recently been put forward as the main agent of the disease. In this new light, some structural details of the human eye, the result of the peculiar evolutionary development, take on an unexpected role in the presentation of the disease. As results of cladistics analysis, the human eye appears as particularly prone to suffering glaucoma as a consequence of the evolutionary path taken. That makes glaucoma essentially a human (and related hominid) scourge. Exclusive features of the human eye compared to other vertebrates involve both the anterior and posterior segment. Those features that facilitate glaucoma in humans are absent in many of the purported animal models for the disease, and this inadequacy further convolutes the mystery of glaucoma. This suggests the division of the animal models into those that mimic the whole disease and those that only reproduce a pertinent histological feature. Unfortunately most animal models are based on high intraocular pressure which excludes most cases of low or moderate pressure. For any animal model, it is important the researcher accurately establishes the constraints of the model in order to avoid jumping to conclusions.

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“…It is formed by a complex, mesh-like array of interlocking 'beams', each of which is essentially a collagen-rich connective tissue sheath surrounding a capillary [1,2]. Together, the beams form an intricate porous structure, through which the RGC axons pass and join together to form the optic nerve.…”

Section: Introductionmentioning

confidence: 99%

Automated segmentation of the lamina cribrosa using Frangi's filter: a novel approach for rapid identification of tissue volume fraction and beam orientation in a trabeculated structure in the eye

Campbell

Coudrillier

Mensah

et al. 2015

J. R. Soc. Interface.

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The lamina cribrosa (LC) is a tissue in the posterior eye with a complex trabecular microstructure. This tissue is of great research interest, as it is likely the initial site of retinal ganglion cell axonal damage in glaucoma. Unfortunately, the LC is difficult to access experimentally, and thus imaging techniques in tandem with image processing have emerged as powerful tools to study the microstructure and biomechanics of this tissue. Here, we present a staining approach to enhance the contrast of the microstructure in micro-computed tomography (micro-CT) imaging as well as a comparison between tissues imaged with micro-CT and second harmonic generation (SHG) microscopy. We then apply a modified version of Frangi's vesselness filter to automatically segment the connective tissue beams of the LC and determine the orientation of each beam. This approach successfully segmented the beams of a porcine optic nerve head from micro-CT in three dimensions and SHG microscopy in two dimensions. As an application of this filter, we present finite-element modelling of the posterior eye that suggests that connective tissue volume fraction is the major driving factor of LC biomechanics. We conclude that segmentation with Frangi's filter is a powerful tool for future image-driven studies of LC biomechanics.

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A biomechanical paradigm for axonal insult within the optic nerve head in aging and glaucoma

Cited by 345 publications

References 167 publications

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Glaucoma as a Tax on Hominid Evolution. Constraints of the Experimental Animal Models of Glaucoma

Automated segmentation of the lamina cribrosa using Frangi's filter: a novel approach for rapid identification of tissue volume fraction and beam orientation in a trabeculated structure in the eye

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