Preclinical Retinal Neurodegeneration in a Model of Multiple Sclerosis

Abstract

Neurodegeneration plays a major role in multiple sclerosis (MS), in which it is thought to be the main determinant of permanent disability. However,therelationshipbetweentheimmuneresponseandtheonsetofneurodegenerationisstillamatterofdebate.Moreover,recentfindings in MS patients raised the question of whether primary neurodegenerative changes can occur in the retina independent of optic nerve inflammation. Using a rat model of MS that frequently leads to optic neuritis, we have investigated the interconnection between neurodegenerative and inflammatory changes in the retina and the optic nerves with special focus on preclinical disease stages. We report that, before manifestation of optic neuritis, characterized by inflammatory infiltration and demyelination of the optic nerve, degeneration of retinal ganglion cell bodies had alreadybegunandultrastructuralsignsofaxondegenerationcouldbedetected.Inaddition,weobservedanearlyactivationofresidentmicroglia in the retina. In the optic nerve, the highest density of activated microglia was found within the optic nerve head. In parallel, localized breakdown in the integrity of the blood-retinal barrier and aberrations in the organization of the blood-brain barrier marker aquaporin-4 in the optic nerves were observed during the preclinical phase, before onset of optic neuritis. From these findings, we conclude that early and subtle inflammatory changes in the retina and/or the optic nerve head reminiscent of those suggested for preclinical MS lesions may initiate the process of neurodegeneration in the retina before major histopathological signs of MS become manifest.

CatWalk gait analysis in a rat model of multiple sclerosis

“…In the same animal model apoptosis of retinal ganglion cells with decline of visual function in electrophysiological recordings was observed in the preclinical phase of EAE. At this time point no histopathological abnormalities were detected in the optic nerve [12, 14]. In MOG-EAE model in mice axonal loss in the spinal cord was detected before clinical manifestation of the disease [15].…”

Tracking changes over time in retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness in multiple sclerosis

“…Another possibility is that RGC somas atrophy before the axons even though in retrograde degeneration, axonal pathology/dysfunction precedes that of ganglion cell body. Fairless et al 25 demonstrated in a rat model of MS, that at the time of significant RGC soma loss, the axons appeared to be intact in numbers but showed ultrastructural signs of degeneration. Recent studies in glaucoma demonstrated the value of measuring macular RGC.…”

Tryptophan-2,3-Dioxygenase (TDO) deficiency is associated with subclinical neuroprotection in a mouse model of multiple sclerosis

“…Bielschowsky’s silver impregnation was performed in order to depict axonal pathology, as previously described55. To further assess axonal degeneration, immunohistochemistry was performed using an antibody against APP as described previously57.…”