CNS axonal degeneration and transport deficits at the optic nerve head precede structural and functional loss of retinal ganglion cells in a mouse model of glaucoma

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dc.creatorMaddineni, Prabhavathi
dc.creatorKasetti, Ramesh B.
dc.creatorPatel, Pinkal D.
dc.creatorMillar, J. Cameron
dc.creatorKiehlbauch, Charles
dc.creatorClark, Abbot F.
dc.creatorZode, Gulab S.
dc.creator.orcid0000-0003-3594-6560 (Clark, Abbot F.)
dc.creator.orcid0000-0002-7823-2595 (Zode, Gulab S.)
dc.date.accessioned2022-11-28T20:48:04Z
dc.date.available2022-11-28T20:48:04Z
dc.date.issued2020-08-27
dc.description.abstractBACKGROUND: Glaucoma is a leading neurodegenerative disease affecting over 70 million individuals worldwide. Early pathological events of axonal degeneration and retinopathy in response to elevated intraocular pressure (IOP) are limited and not well-defined due to the lack of appropriate animal models that faithfully replicate all the phenotypes of primary open angle glaucoma (POAG), the most common form of glaucoma. Glucocorticoid (GC)-induced ocular hypertension (OHT) and its associated iatrogenic open-angle glaucoma share many features with POAG. Here, we characterized a novel mouse model of GC-induced OHT for glaucomatous neurodegeneration and further explored early pathological events of axonal degeneration in response to elevated IOP. METHODS: C57BL/6 J mice were periocularly injected with either vehicle or the potent GC, dexamethasone 21-acetate (Dex) once a week for 10 weeks. Glaucoma phenotypes including IOP, outflow facility, structural and functional loss of retinal ganglion cells (RGCs), optic nerve (ON) degeneration, gliosis, and anterograde axonal transport deficits were examined at various stages of OHT. RESULTS: Prolonged treatment with Dex leads to glaucoma in mice similar to POAG patients including IOP elevation due to reduced outflow facility and dysfunction of trabecular meshwork, progressive ON degeneration and structural and functional loss of RGCs. Lowering of IOP rescued Dex-induced ON degeneration and RGC loss, suggesting that glaucomatous neurodegeneration is IOP dependent. Also, Dex-induced neurodegeneration was associated with activation of astrocytes, axonal transport deficits, ON demyelination, mitochondrial accumulation and immune cell infiltration in the optic nerve head (ONH) region. Our studies further show that ON degeneration precedes structural and functional loss of RGCs in Dex-treated mice. Axonal damage and transport deficits initiate at the ONH and progress toward the distal end of ON and target regions in the brain (i.e. superior colliculus). Most of anterograde transport was preserved during initial stages of axonal degeneration (30% loss) and complete transport deficits were only observed at the ONH during later stages of severe axonal degeneration (50% loss). CONCLUSIONS: These findings indicate that ON degeneration and transport deficits at the ONH precede RGC structural and functional loss and provide a new potential therapeutic window for rescuing neuronal loss and restoring health of damaged axons in glaucoma.
dc.description.sponsorshipThese studies were supported by the National Institutes of Health; EY022077 (GSZ), EY028616 (GSZ), EY026177 (GSZ) and EY016242 (AFC) and the Bright Focus Glaucoma Foundation (GSZ).
dc.identifier.citationMaddineni, P., Kasetti, R. B., Patel, P. D., Millar, J. C., Kiehlbauch, C., Clark, A. F., & Zode, G. S. (2020). CNS axonal degeneration and transport deficits at the optic nerve head precede structural and functional loss of retinal ganglion cells in a mouse model of glaucoma. Molecular neurodegeneration, 15(1), 48. https://doi.org/10.1186/s13024-020-00400-9
dc.identifier.issn1750-1326
dc.identifier.issue1
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31989
dc.identifier.volume15
dc.publisherBioMed Central Ltd.
dc.relation.urihttps://doi.org/10.1186/s13024-020-00400-9
dc.rights.holder© The Author(s). 2020.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceMolecular Neurodegeneration
dc.subjectoptic nerve head axonal degeneration
dc.subjectanterograde transport deficits
dc.subjectglucocorticoid-induced glaucoma
dc.subjectintraocular pressure
dc.subjectmouse model of glaucoma
dc.subjectneurodegeneration
dc.subjectocular hypertension
dc.subjectoptic nerve degeneration
dc.subjectpoag
dc.subjectretinal ganglion cell loss
dc.subjecttrabecular meshwork
dc.subject.meshAnimals
dc.subject.meshAxonal Transport / physiology
dc.subject.meshDisease Models, Animal
dc.subject.meshGlaucoma / pathology
dc.subject.meshMice
dc.subject.meshMice, Inbred C57BL
dc.subject.meshNerve Degeneration / pathology
dc.subject.meshOptic Disk / pathology
dc.subject.meshRetinal Ganglion Cells / pathology
dc.titleCNS axonal degeneration and transport deficits at the optic nerve head precede structural and functional loss of retinal ganglion cells in a mouse model of glaucoma
dc.typeArticle
dc.type.materialtext

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