Autophagy in the Aging and Experimental Ocular Hypertensive Mouse Model.
Nettesheim April, Dixon Angela, Shim Myoung Sup, Coyne Aislyn, Walsh Molly, Liton Paloma B
AI Summary
This study found dysregulated autophagy in older, ocular hypertensive mice, suggesting this contributes to glaucoma neurodegeneration and increased retinal ganglion cell loss.
Abstract
Purpose
To investigate autophagy in the outflow pathway and ganglion cell layer in the aging and ocular hypertensive mouse.
Methods
Both 4-month-old and 18-month-old C57BL/6J and GFP-LC3 mice were subjected to unilateral injection of hypertonic saline into a limbal vein, causing sclerosis of the outflow pathway and subsequent elevation of intraocular pressure (IOP). IOP was measured on a weekly basis using a rebound tonometer. Protein expression levels of LC3B, Lamp1, and p62 were evaluated by western blot and/or immunofluorescence. Retinal ganglion cell (RGC) count was performed in whole retinal flat mounts using an anti-Brn3a antibody. Optic nerves were fixed with 4% paraformaldehyde and resin-embedded for axon counts and electron microscopy.
Results
In contrast to 18-month-old mice, which developed sustained elevated IOP with a single injection, 4-month-old mice were refractory to high elevations of IOP. Interestingly, both the percentage of animals that developed elevated IOP and the mean ∆IOP were significantly higher in the transgenic mice compared to C57BL/6J. Immunofluorescence and western blot analysis showed dysregulated autophagy in the iridocorneal and retina tissues from 18-month-old mice compared to 4-month-old ones. Moreover, the LC3-II/LC3-I ratio correlated with IOP. As expected, injected hypertensive eyes displayed axonal degeneration and RGC death. RGC and axon loss were significantly exacerbated with aging, especially when combined with GFP-LC3 expression. Autophagic structures were observed in the degenerating axons.
Conclusions
Our results indicate dysregulation of autophagy in the trabecular meshwork and retinal tissues with aging and suggest that such dysregulation of autophagy contributes to neurodegeneration in glaucoma.
MeSH Terms
Shields Classification
Key Concepts6
In a mouse model, 18-month-old mice developed sustained elevated intraocular pressure (IOP) with a single injection of hypertonic saline into a limbal vein, while 4-month-old mice were refractory to high elevations of IOP.
In a mouse model of ocular hypertension, both the percentage of animals that developed elevated intraocular pressure (IOP) and the mean ∆IOP were significantly higher in transgenic GFP-LC3 mice compared to C57BL/6J mice.
Immunofluorescence and western blot analysis in an experimental mouse model showed dysregulated autophagy in the iridocorneal and retina tissues from 18-month-old mice compared to 4-month-old mice.
In an experimental mouse model, the LC3-II/LC3-I ratio correlated with intraocular pressure (IOP).
In an experimental mouse model, injected hypertensive eyes displayed axonal degeneration and retinal ganglion cell (RGC) death, with RGC and axon loss significantly exacerbated with aging, especially when combined with GFP-LC3 expression.
Autophagic structures were observed in the degenerating axons of injected hypertensive eyes in an experimental mouse model.
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