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A method to quantify regional axonal transport blockade at the optic nerve head after short term intraocular pressure elevation in mice.
Exp Eye Res. 2020 07; 196:108035.EE

Abstract

Axonal transport blockade is an initial step in retinal ganglion cell (RGC) degeneration in glaucoma and targeting maintenance of normal axonal transport could confer neuroprotection. We present an objective, quantitative method for assessing axonal transport blockade in mouse glaucoma models. Intraocular pressure (IOP) was elevated unilaterally in CD1 mice for 3 days using intracameral microbead injection. Longitudinal sections of optic nerve head (ONH) were immunofluorescently labeled for myelin basic protein (MBP) and amyloid precursor protein (APP), which is transported predominantly orthograde by neurons. The beginning of the myelin transition zone, visualized with the MBP label, was more posterior with elevated IOP, 288.8 ± 40.9 μm, compared to normotensive control eyes, 228.7 ± 32.7 μm (p = 0.030, N = 6 pairs). Glaucomatous regional APP accumulations in retina, prelaminar ONH, unmyelinated ONH, and myelinated optic nerve were identified by objective qualification of pixels with fluorescent intensity greater than the 97.5th percentile value of control eyes (suprathreshold pixels). This method segregated images with APP blockade from those with normal transport of APP. The fraction of suprathreshold pixels was significantly higher following IOP elevation than in normotensive controls in the unmyelinated ONH and myelinated nerve regions (paired analyses, p = 0.02 and 0.003, respectively, N = 12), but not in retina or prelaminar ONH (p = 0.91 and 0.08, respectively). The mean intensity of suprathreshold pixels was also significantly greater in glaucoma than in normotensive controls in prelaminar ONH, unmyelinated ONH and myelinated optic nerve (p = 0.01, 0.01, 0.002, respectively). Using this method, subconjunctival glyceraldehyde, which is known to worsen long-term RGC loss with IOP elevation, also produced greater APP blockade, but not statistically significant compared to glaucoma alone. Systemic losartan, which aids RGC axonal survival in glaucoma, reduced APP blockade, but not statistically significant compared to glaucoma alone. The method provides a short-term assessment of axonal injury for use in initial tests of neuroprotective therapies that may beneficially affect RGC transport in animal models of glaucoma.

Authors+Show Affiliations

From the Glaucoma Center of Excellence, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.From the Glaucoma Center of Excellence, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.From the Glaucoma Center of Excellence, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.From the Glaucoma Center of Excellence, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.From the Glaucoma Center of Excellence, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.From the Glaucoma Center of Excellence, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.From the Glaucoma Center of Excellence, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.From the Glaucoma Center of Excellence, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.From the Glaucoma Center of Excellence, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: hquigley@jhmi.edu.

Pub Type(s)

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

Language

eng

PubMed ID

32353427

Citation

Korneva, Arina, et al. "A Method to Quantify Regional Axonal Transport Blockade at the Optic Nerve Head After Short Term Intraocular Pressure Elevation in Mice." Experimental Eye Research, vol. 196, 2020, p. 108035.
Korneva A, Schaub J, Jefferys J, et al. A method to quantify regional axonal transport blockade at the optic nerve head after short term intraocular pressure elevation in mice. Exp Eye Res. 2020;196:108035.
Korneva, A., Schaub, J., Jefferys, J., Kimball, E., Pease, M. E., Nawathe, M., Johnson, T. V., Pitha, I., & Quigley, H. (2020). A method to quantify regional axonal transport blockade at the optic nerve head after short term intraocular pressure elevation in mice. Experimental Eye Research, 196, 108035. https://doi.org/10.1016/j.exer.2020.108035
Korneva A, et al. A Method to Quantify Regional Axonal Transport Blockade at the Optic Nerve Head After Short Term Intraocular Pressure Elevation in Mice. Exp Eye Res. 2020;196:108035. PubMed PMID: 32353427.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A method to quantify regional axonal transport blockade at the optic nerve head after short term intraocular pressure elevation in mice. AU - Korneva,Arina, AU - Schaub,Julie, AU - Jefferys,Joan, AU - Kimball,Elizabeth, AU - Pease,Mary Ellen, AU - Nawathe,Manasi, AU - Johnson,Thomas V, AU - Pitha,Ian, AU - Quigley,Harry, Y1 - 2020/04/27/ PY - 2020/02/20/received PY - 2020/03/28/revised PY - 2020/04/08/accepted PY - 2020/5/1/pubmed PY - 2021/1/9/medline PY - 2020/5/1/entrez KW - Amyloid precursor protein KW - Axonal transport KW - Glaucoma KW - Glyceraldehyde KW - Immunofluorescence KW - Losartan KW - Mouse SP - 108035 EP - 108035 JF - Experimental eye research JO - Exp Eye Res VL - 196 N2 - Axonal transport blockade is an initial step in retinal ganglion cell (RGC) degeneration in glaucoma and targeting maintenance of normal axonal transport could confer neuroprotection. We present an objective, quantitative method for assessing axonal transport blockade in mouse glaucoma models. Intraocular pressure (IOP) was elevated unilaterally in CD1 mice for 3 days using intracameral microbead injection. Longitudinal sections of optic nerve head (ONH) were immunofluorescently labeled for myelin basic protein (MBP) and amyloid precursor protein (APP), which is transported predominantly orthograde by neurons. The beginning of the myelin transition zone, visualized with the MBP label, was more posterior with elevated IOP, 288.8 ± 40.9 μm, compared to normotensive control eyes, 228.7 ± 32.7 μm (p = 0.030, N = 6 pairs). Glaucomatous regional APP accumulations in retina, prelaminar ONH, unmyelinated ONH, and myelinated optic nerve were identified by objective qualification of pixels with fluorescent intensity greater than the 97.5th percentile value of control eyes (suprathreshold pixels). This method segregated images with APP blockade from those with normal transport of APP. The fraction of suprathreshold pixels was significantly higher following IOP elevation than in normotensive controls in the unmyelinated ONH and myelinated nerve regions (paired analyses, p = 0.02 and 0.003, respectively, N = 12), but not in retina or prelaminar ONH (p = 0.91 and 0.08, respectively). The mean intensity of suprathreshold pixels was also significantly greater in glaucoma than in normotensive controls in prelaminar ONH, unmyelinated ONH and myelinated optic nerve (p = 0.01, 0.01, 0.002, respectively). Using this method, subconjunctival glyceraldehyde, which is known to worsen long-term RGC loss with IOP elevation, also produced greater APP blockade, but not statistically significant compared to glaucoma alone. Systemic losartan, which aids RGC axonal survival in glaucoma, reduced APP blockade, but not statistically significant compared to glaucoma alone. The method provides a short-term assessment of axonal injury for use in initial tests of neuroprotective therapies that may beneficially affect RGC transport in animal models of glaucoma. SN - 1096-0007 UR - https://www.unboundmedicine.com/medline/citation/32353427/A_method_to_quantify_regional_axonal_transport_blockade_at_the_optic_nerve_head_after_short_term_intraocular_pressure_elevation_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4835(20)30294-3 DB - PRIME DP - Unbound Medicine ER -