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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.
Mol Neurodegener. 2020 08 27; 15(1):48.MN

Abstract

BACKGROUND

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.

Authors+Show Affiliations

Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, IREB-535, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, IREB-535, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, IREB-535, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, IREB-535, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, IREB-535, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, IREB-535, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, IREB-535, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA. gulab.zode@unthsc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32854767

Citation

Maddineni, Prabhavathi, et al. "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, vol. 15, no. 1, 2020, p. 48.
Maddineni P, Kasetti RB, Patel PD, et al. 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. Mol Neurodegener. 2020;15(1):48.
Maddineni, 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
Maddineni P, et al. 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. Mol Neurodegener. 2020 08 27;15(1):48. PubMed PMID: 32854767.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Maddineni,Prabhavathi, AU - Kasetti,Ramesh B, AU - Patel,Pinkal D, AU - Millar,J Cameron, AU - Kiehlbauch,Charles, AU - Clark,Abbot F, AU - Zode,Gulab S, Y1 - 2020/08/27/ PY - 2020/06/09/received PY - 2020/08/18/accepted PY - 2020/8/29/entrez PY - 2020/8/29/pubmed PY - 2021/8/27/medline KW - And optic nerve head axonal degeneration KW - Anterograde transport deficits KW - Glucocorticoid-induced glaucoma KW - Intraocular pressure KW - Mouse model of glaucoma KW - Neurodegeneration KW - Ocular hypertension KW - Optic nerve degeneration KW - POAG KW - Retinal ganglion cell loss KW - Trabecular meshwork SP - 48 EP - 48 JF - Molecular neurodegeneration JO - Mol Neurodegener VL - 15 IS - 1 N2 - BACKGROUND: 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. SN - 1750-1326 UR - https://www.unboundmedicine.com/medline/citation/32854767/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_ L2 - https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-020-00400-9 DB - PRIME DP - Unbound Medicine ER -