Anterograde Tract Tracing for Assaying Axonopathy and Transport Deficits in Glaucoma

Crish, Samuel D.; Schofield, Brett R.

doi:10.1007/978-1-4939-7407-8_15

Cited by 7 publications

(5 citation statements)

References 31 publications

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“…In this study, significant reductions in PERG P1 and N2 amplitudes occurred at younger ages in 3xTg mice, and with greater severity than agematched controls. These perturbations in 3xTg mouse RGC function did not likely result from upstream loss of outer retinal cell input to RGCs, as our fERG data confirmed that 3xTg mice exhibited normal photoreceptor responses [105,106]. Additionally, fERG data indicated that both 3xTg and control mice exhibited normal age-related changes in the function of bipolar cells-the interneurons conveying visual signals between photoreceptors and RGCs [114].…”

Section: Discussionsupporting

confidence: 65%

“…SC images were taken with a 5x objective at a resolution of 1.3 m × 1.3 m per pixel. Integrity of axonal transport was determined by percent area fraction coverage of CTB tracer across the rostrocaudal extent of superficial SC and was computed using a custom-built macro [93,106] for NIH Image J [93,106]; this macro is freely available for use via this reference [93]. The integrity of RGC synaptic terminal distribution across the superficial SC was determined by computing percent area fraction of VGlut2 label in the same way [107].…”

Section: Microscopy and Quantification Of Rgc Density And Axonal Tran...mentioning

confidence: 99%

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Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer’s Disease Mice

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Schuller

Smith

et al. 2022

JAD

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Background: Visual disturbances often precede cognitive dysfunction in patients with Alzheimer’s disease (AD) and may coincide with early accumulation of amyloid-β (Aβ) protein in the retina. These findings have inspired critical research on in vivo ophthalmic Aβ imaging for disease biomarker detection but have not fully answered mechanistic questions on how retinal pathology affects visual signaling between the eye and brain. Objective: The goal of this study was to provide a functional and structural assessment of eye-brain communication between retinal ganglion cell (RGCs) and their primary projection target, the superior colliculus, in female and male 3xTg-AD mice across disease stages. Methods: Retinal electrophysiology, axonal transport, and immunofluorescence were used to determine RGC projection integrity, and retinal and collicular Aβ levels were assessed with advanced protein quantitation techniques. Results: 3xTg mice exhibited nuanced deficits in RGC electrical signaling, axonal transport, and synaptic integrity that exceeded normal age-related decrements in RGC function in age- and sex-matched healthy control mice. These deficits presented in sex-specific patterns among 3xTg mice, differing in the timing and severity of changes. Conclusion: These data support the premise that retinal Aβ is not just a benign biomarker in the eye, but may contribute to subtle, nuanced visual processing deficits. Such disruptions might enhance the biomarker potential of ocular amyloid and differentiate patients with incipient AD from patients experiencing normal age-related decrements in visual function.

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Section: Discussionsupporting

confidence: 65%

Section: Microscopy and Quantification Of Rgc Density And Axonal Tran...mentioning

confidence: 99%

Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer’s Disease Mice

Frame

Schuller

Smith

et al. 2022

JAD

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“…We evaluated transport of cholera toxin subunit B (CTB) from the retina to the superior colliculus (SC), the primary central projection for RGCs in rodents, in rats that received vehicle or BIRB 796 as anterograde axonal transport is compromised early in models of glaucoma 4,[41][42][43][44] . We verified RGC uptake and initial transport of fluorescently labeled CTB in RGC axons from naïve, vehicle-saline, vehicle-microbead, BIRB 796-saline and BIRB 796-microbead retinas ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Of Mice and Monkeys: Neuroprotective Efficacy of the p38 Inhibitor BIRB 796 Depends on Model Duration in Experimental Glaucoma

Lambert

Pasini

Collyer

et al. 2020

Sci Rep

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Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). Early progression involves retinal ganglion cell (RGC) axon dysfunction that precedes frank degeneration. Previously we demonstrated that p38 MAPK inhibition abates axonal dysfunction and slows degeneration in the inducible microbead occlusion model of glaucoma in rat. Here, we assessed the neuroprotective effect of topical eye delivery of the p38 MAPK inhibitor BIRB 796 in three models of glaucoma (microbead occlusion in rat and squirrel monkey and the genetic DBA/2 J mouse model) with distinct durations of IOP elevation. While BIRB 796 did not influence IOP, treatment over four weeks in rats prevented degradation of anterograde axonal transport to the superior colliculus and degeneration in the optic nerve. Treatment over months in the chronic DBA/2 J model and in the squirrel monkey model reduced expression and activation of p38 downstream targets in the retina and brain but did not rescue RGC axon transport or degeneration, suggesting the efficacy of BIRB 796 in preventing associated degeneration of the RGC projection depends on the duration of the experimental model. These results emphasize the importance of evaluating potential therapeutic compounds for neuroprotection in multiple models using elongated treatment paradigms for an accurate assessment of efficacy. Glaucoma is the primary source of permanent sightlessness around the world 1 , and is second only to cataract in producing vision loss. Estimates suggest that by 2020 over 75 million individuals will have glaucoma and that more than 10 million of those will already suffer from irreversible blindness 1-3. In glaucoma, stress associated with sensitivity to intraocular pressure (IOP) is transmitted at the optic nerve head, selectively targeting retinal ganglion cells (RGCs) and their axons 4,5. While age is a key risk factor, IOP is the only modifiable risk factor and the singular focus for clinical intervention 6. The use of topical IOP-lowering drugs is the first line treatment for glaucoma 7. Glaucoma progression can be slowed by reducing IOP, however RGC degeneration (and vision loss) continues for many. For nearly half the patients with glaucoma taking medications to reduce IOP, the disease will continue to worsen 6,8,9. Neurodegeneration in glaucoma is similar to other age-related neurodegenerative disorders like amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease in that axonal function is compromised prior to death of neurons 10-16. Deterioration of anterograde transport from RGCs to central targets in the brain arises early in animal models of glaucoma; degradation is followed by somatic drop-out in the retina subsequent to axonal loss in the optic nerve 17-19. Experimental interventions that preserve axonal transport can suspend or stop subsequent degeneration of axons and cell bodies 20-22. Given this progression, it is appropriate that the identification of neuroprotective therapies tha...

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“…Deficits in anterograde transport to ganglion cell axonal targets in subcortical structures is an early response to elevated IOP in rodent models of glaucoma that precedes frank axon degeneration in the optic nerve; both precede ganglion cell body loss in the retina 2,13,36 . While in rodents the majority (~95%) of ganglion cells axons project contralaterally, ganglion cells in SMs and other primates project ipsilaterally and contralaterally in about equal (50:50) proportion 37 .…”

Section: Resultsmentioning

confidence: 99%

Towards A Microbead Occlusion Model of Glaucoma for a Non-Human Primate

Lambert

Carlson

Ghose

et al. 2019

Sci Rep

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Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). The disease causes vision loss through the degeneration of retinal ganglion cell neurons and their axons in the optic nerve. Using an inducible model of glaucoma, we elevated IOP in the squirrel monkey ( Saimiri boliviensis ) using intracameral injection of 35 μm polystyrene microbeads and measured common pathogenic outcomes in the optic projection. A 42% elevation in IOP over 28 weeks reduced anterograde transport of fluorescently-labeled cholera toxin beta from retina to the lateral geniculate nucleus (60% decrease), and to the superior colliculus (49% decrease). Pressure also reduced survival of ganglion cellaxons in the optic nerve by 22%. The same elevation caused upregulation of proteins associated with glaucomatous neurodegeneration in the retina and optic nerve, including complement 1q, interleukin 6, and brain-derived neurotrophic factor. That axon degeneration in the nerve lagged deficits in anterograde transport is consistent with progression in rodent models, while the observed protein changes also occur in tissue from human glaucoma patients. Thus, microbead occlusion in a non-human primate with a visual system similar to our own represents an attractive model to investigate neurodegenerative mechanisms and therapeutic interventions for glaucoma.

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Anterograde Tract Tracing for Assaying Axonopathy and Transport Deficits in Glaucoma

Cited by 7 publications

References 31 publications

Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer’s Disease Mice

Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer’s Disease Mice

Of Mice and Monkeys: Neuroprotective Efficacy of the p38 Inhibitor BIRB 796 Depends on Model Duration in Experimental Glaucoma

Towards A Microbead Occlusion Model of Glaucoma for a Non-Human Primate

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