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Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma.
Exp Eye Res. 2016 09; 150:22-33.EE

Abstract

Glaucoma challenges the survival of retinal ganglion cell axons in the optic nerve through processes dependent on both aging and ocular pressure. Relevant stressors likely include complex interplay between axons and astrocytes, both in the retina and optic nerve. In the DBA/2J mouse model of pigmentary glaucoma, early progression involves axonopathy characterized by loss of functional transport prior to outright degeneration. Here we describe novel features of early pathogenesis in the DBA/2J nerve. With age the cross-sectional area of the nerve increases; this is associated generally with diminished axon packing density and survival and increased glial coverage of the nerve. However, for nerves with the highest axon density, as the nerve expands mean cross-sectional axon area enlarges as well. This early expansion was marked by disorganized axoplasm and accumulation of hyperphosphorylated neurofilamants indicative of axonopathy. Axon expansion occurs without loss up to a critical threshold for size (about 0.45-0.50 μm(2)), above which additional expansion tightly correlates with frank loss of axons. As well, early axon expansion prior to degeneration is concurrent with decreased astrocyte ramification with redistribution of processes towards the nerve edge. As axons expand beyond the critical threshold for loss, glial area resumes an even distribution from the center to edge of the nerve. We also found that early axon expansion is accompanied by reduced numbers of mitochondria per unit area in the nerve. Finally, our data indicate that both IOP and nerve expansion are associated with axon enlargement and reduced axon density for aged nerves. Collectively, our data support the hypothesis that diminished bioenergetic resources in conjunction with early nerve and glial remodeling could be a primary inducer of progression of axon pathology in glaucoma.

Authors+Show Affiliations

Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37205, United States.Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, United States.Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, United States.Biotherapeutics & Regenerative Medicine Research Center, Houston Methodist, Houston, TX 77030, United States.Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37205, United States. Electronic address: david.j.calkins@vanderbilt.edu.

Pub Type(s)

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

Language

eng

PubMed ID

26646560

Citation

Cooper, Melissa L., et al. "Early Astrocyte Redistribution in the Optic Nerve Precedes Axonopathy in the DBA/2J Mouse Model of Glaucoma." Experimental Eye Research, vol. 150, 2016, pp. 22-33.
Cooper ML, Crish SD, Inman DM, et al. Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma. Exp Eye Res. 2016;150:22-33.
Cooper, M. L., Crish, S. D., Inman, D. M., Horner, P. J., & Calkins, D. J. (2016). Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma. Experimental Eye Research, 150, 22-33. https://doi.org/10.1016/j.exer.2015.11.016
Cooper ML, et al. Early Astrocyte Redistribution in the Optic Nerve Precedes Axonopathy in the DBA/2J Mouse Model of Glaucoma. Exp Eye Res. 2016;150:22-33. PubMed PMID: 26646560.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma. AU - Cooper,Melissa L, AU - Crish,Samuel D, AU - Inman,Denise M, AU - Horner,Philip J, AU - Calkins,David J, Y1 - 2015/12/02/ PY - 2015/08/28/received PY - 2015/11/12/revised PY - 2015/11/23/accepted PY - 2015/12/10/entrez PY - 2015/12/10/pubmed PY - 2017/6/16/medline KW - Astrocyte KW - Axonopathy KW - Glaucoma KW - Gliosis KW - Neurodegeneration KW - Retinal ganglion cell SP - 22 EP - 33 JF - Experimental eye research JO - Exp Eye Res VL - 150 N2 - Glaucoma challenges the survival of retinal ganglion cell axons in the optic nerve through processes dependent on both aging and ocular pressure. Relevant stressors likely include complex interplay between axons and astrocytes, both in the retina and optic nerve. In the DBA/2J mouse model of pigmentary glaucoma, early progression involves axonopathy characterized by loss of functional transport prior to outright degeneration. Here we describe novel features of early pathogenesis in the DBA/2J nerve. With age the cross-sectional area of the nerve increases; this is associated generally with diminished axon packing density and survival and increased glial coverage of the nerve. However, for nerves with the highest axon density, as the nerve expands mean cross-sectional axon area enlarges as well. This early expansion was marked by disorganized axoplasm and accumulation of hyperphosphorylated neurofilamants indicative of axonopathy. Axon expansion occurs without loss up to a critical threshold for size (about 0.45-0.50 μm(2)), above which additional expansion tightly correlates with frank loss of axons. As well, early axon expansion prior to degeneration is concurrent with decreased astrocyte ramification with redistribution of processes towards the nerve edge. As axons expand beyond the critical threshold for loss, glial area resumes an even distribution from the center to edge of the nerve. We also found that early axon expansion is accompanied by reduced numbers of mitochondria per unit area in the nerve. Finally, our data indicate that both IOP and nerve expansion are associated with axon enlargement and reduced axon density for aged nerves. Collectively, our data support the hypothesis that diminished bioenergetic resources in conjunction with early nerve and glial remodeling could be a primary inducer of progression of axon pathology in glaucoma. SN - 1096-0007 UR - https://www.unboundmedicine.com/medline/citation/26646560/Early_astrocyte_redistribution_in_the_optic_nerve_precedes_axonopathy_in_the_DBA/2J_mouse_model_of_glaucoma_ DB - PRIME DP - Unbound Medicine ER -