Retinal Ganglion Cells Resistant to Advanced Glaucoma: A Postmortem Study of Human Retinas with the Carbocyanine Dye DiI

Pavlidis, Mitrofanis; Stupp, Tobias; Naskar, Rita; Cengiz, Cani; Thanos, Solon

doi:10.1167/iovs.03-0614

Cited by 85 publications

(53 citation statements)

References 36 publications

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“…As in previous studies that used DiI to label human retinas [33,42], the dye was found to label cells located up to 5 mm from the point of application.…”

Section: Methodssupporting

confidence: 71%

“…To visualize the ganglion cell axons and dendrites, paraformaldehyde-fixed retinas were labeled with the lipophilic carbocyanine dye, DiI (1,1′-dioctadecyl-3,3,3′,3′ tetramethylindocarbocyanine perchlorate; Molecular Probes, Eugene, Ore.) [16,33,42]. Morphometric changes were assessed by examining the number of dendritic bifurcations and the extent of dendritic branching of both midget and parasol cells throughout the retinal eccentricity.…”

Section: Introductionmentioning

confidence: 99%

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Pathological changes in human retinal ganglion cells associated with diabetic and hypertensive retinopathy

Meyer-Rüsenberg

Pavlidis

Stupp

et al. 2006

Graefes Arch Clin Exp Ophthalmol

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“…As in previous studies that used DiI to label human retinas [33,42], the dye was found to label cells located up to 5 mm from the point of application.…”

Section: Methodssupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Pathological changes in human retinal ganglion cells associated with diabetic and hypertensive retinopathy

Meyer-Rüsenberg

Pavlidis

Stupp

et al. 2006

Graefes Arch Clin Exp Ophthalmol

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“…Neuritic beading is observed in various pathological conditions (23)(24)(25)(26)(27)(28)(29)(30)(31). Our current results indicate that neuritic beads represent the accumulation of vesicular cargo and transport proteins following damage to the transport mechanisms by activated microglia.…”

Section: Discussionmentioning

confidence: 53%

Neuritic Beading Induced by Activated Microglia Is an Early Feature of Neuronal Dysfunction Toward Neuronal Death by Inhibition of Mitochondrial Respiration and Axonal Transport

Takeuchi

Mizuno

Zhang

et al. 2005

Journal of Biological Chemistry

261

215

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Recent studies suggest that excitotoxicity may contribute to neuronal damage in neurodegenerative diseases including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. Activated microglia have been observed around degenerative neurons in these diseases, and they are thought to act as effector cells in the degeneration of neural cells in the central nervous system. Neuritic beading, focal bead-like swellings in the dendrites and axons, is a neuropathological sign in epilepsy, trauma, ischemia, aging, and neurodegenerative diseases. Previous reports showed that neuritic beading is induced by various stimuli including glutamate or nitric oxide and is a neuronal response to harmful stimuli. However, the precise physiologic significance of neuritic beading is unclear. We provide evidence that neuritic beading induced by activated microglia is a feature of neuronal cell dysfunction toward neuronal death, and the neurotoxicity of activated microglia is mediated through N-methyl-D-aspartate (NMDA) receptor signaling. Neuritic beading occurred concordant with a rapid drop in intracellular ATP levels and preceded neuronal death. The actual neurite beads consisted of collapsed cytoskeletal proteins and motor proteins arising from impaired neuronal transport secondary to cellular energy loss. The drop in intracellular ATP levels was because of the inhibition of mitochondrial respiratory chain complex IV activity downstream of NMDA receptor signaling. Blockage of NMDA receptors nearly completely abrogated mitochondrial dysfunction and neurotoxicity. Thus, neuritic beading induced by activated microglia occurs through NMDA receptor signaling and represents neuronal cell dysfunction preceding neuronal death. Blockage of NMDA receptors may be an effective therapeutic approach for neurodegenerative diseases.

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“…In neither of the glaucoma animal models was the loss of axons complete, as there appears to be a population of RGC that persist is in human glaucoma (Pavlidis et al, 2003). Since in healthy ONs oligodendrocytes myelinate multiple axons, it is possible that all the oligodendrocytes that remained in the glaucomatous ONs still maintained at least one axonal contact.…”

Section: Discussionmentioning

confidence: 99%

Glaucomatous optic nerve injury involves early astrocyte reactivity and late oligodendrocyte loss

Son

Soto

Oglesby

et al. 2010

Glia

114

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Glaucoma, a neurodegenerative disease affecting retinal ganglion cells (RGC), is a leading cause of blindness. Since gliosis is common in neurodegenerative disorders, it is important to describe the changes occurring in various glial populations in glaucoma animal models in relation to axon loss, as only changes that occur early are likely to be useful therapeutic targets. Here, we describe changes occurring in glia within the myelinated portion of the optic nerve (ON) in both DBA/2J mice and in a rat ocular hypertension model. In both glaucoma animal models, we found only a modest loss of oligodendrocytes that occurred after axons had already degenerated. In DBA/2J mice there was proliferation of oligodendrocyte precursor cells (OPCs) and new oligodendrocyte generation. Activation of microglia was detected only in highly degenerated DBA/2J ONs. In contrast, a large increase in astrocyte reactivity occurred early in both animal models. These results are consistent with astrocytes playing a prominent role in regulating axon loss in glaucoma.

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Retinal Ganglion Cells Resistant to Advanced Glaucoma: A Postmortem Study of Human Retinas with the Carbocyanine Dye DiI

Abstract: The data suggest that the few ganglion cells that survive the elevated intraocular pressure associated with loss of visual function display morphologic changes that are manifested both on the cell body and on their intraretinal processes, including axons and dendrites.

Cited by 85 publications

References 36 publications

Pathological changes in human retinal ganglion cells associated with diabetic and hypertensive retinopathy

Pathological changes in human retinal ganglion cells associated with diabetic and hypertensive retinopathy

Neuritic Beading Induced by Activated Microglia Is an Early Feature of Neuronal Dysfunction Toward Neuronal Death by Inhibition of Mitochondrial Respiration and Axonal Transport

Glaucomatous optic nerve injury involves early astrocyte reactivity and late oligodendrocyte loss

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