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Jacqueline Reinhard, Susanne Wiemann, Julia Woestmann, Stephanie C Joachim, Heiko Schmid, Yingchun Wang, Gregory Downey, Andreas Faissner; Neurodegeneration, reactive gliosis and complement activation in glaucomatous protein tyrosine phosphatase Meg2 deficient mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2419.
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© ARVO (1962-2015); The Authors (2016-present)
Glaucoma is one of the leading causes of blindness worldwide, yet the molecular mechanisms that initiate retinal ganglion cell and optic nerve degeneration remain elusive. In several animal models of glaucoma disease it was shown that reactive gliosis and complement activation are implicated in glaucomatous neurodegeneration. In the present study we report neurodegeneration, reactive gliosis and complement activation in glaucomatous transgenic PTP-Meg2 heterozygous (HET) mice.
Intraocular pressure was evaluated in aging PTP-Meg2 HET and control wildtype (WT) animals (n>6/group). Immunohistochemistry, electron microscopy, protein biochemical and molecular biological analyses (n>3/group) as well as scotopic electroretinogram (ERG) recordings (n=4/group) were used to characterize neurodegeneration, reactive gliosis and complement activation in PTP-Meg2 HET mice. Statistical analysis was performed using students t-test.
PTP-Meg2 HET mice developed a significant progressive intraocular pressure elevation upon 10 weeks of age (p<0.001). At one year of age, HET animals exhibit a significant loss of Brn3a-positive retinal ganglion cells (p<0.01). Moreover, optic nerve degeneration was demonstrated. ERG recordings revealed that PTP-Meg2 HET mice exhibit significant reduced a-wave (p<0.05 at 0.3, 1 and 25 cd*s/m2) and b-wave (p<0.01 at 0.1 and 1 cd*s/m2; p<0.05 at 0.3 and 3 cd*s/m2) amplitudes as well as implicit time to peak prolongation (p<0.01 at 25 cd*s/m2; p<0.05 at 1 and 10 cd*s/m2), suggesting progressive retinal damage. Immunohistochemical stainings verified a significant upregulation of the glial markers GFAP (p<0.01 central; p<0.001 peripheral) and vimentin (p<0.05 central; p<0.01 peripheral) in glaucomatous retinae. Moreover, a significantly increased number of Iba1-positive microglia (p<0.01) was observed in the inner plexiform layer. Finally, an upregulation of C1q and C3 complement components was noted in HET retinae.
Our results demonstrate that PTP-Meg2 deficient mice exhibit neurodegeneration, reactive gliosis and complement activation. In conclusion, PTP-Meg2 heterozygous mice may serve as a new powerful animal model to study the pathomechanisms involved in onset and progression of glaucoma disease.
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