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Sabrina Reinehr, Johanna Dörner, Dennis Koch, Christina Voss, Rudolf Fuchshofer, Burkhard Dick, Stephanie C Joachim; Timeline of retinal ganglion cell loss and complement response in βb1-CTGF glaucoma mice. Invest. Ophthalmol. Vis. Sci. 2019;60(9):649.
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© ARVO (1962-2015); The Authors (2016-present)
To understand the pathology of primary open-angle glaucoma more precisely, appropriate models are needed. The βb1-CTGF mouse seems promising to mimic intraocular pressure-dependent loss of retinal ganglion cells (RGCs) and optic nerve degeneration. Here, we investigated the timeline of disease progression and complement response.
At 5, 10, and 15 weeks, retinal cross-sections (n=7-9/group) were prepared from βb1-CTGF and wildtype (WT) mice. Immunohistology was performed with markers against retinal ganglion cells (RGCs; Brn-3a), apoptosis (cleaved caspase 3), and complement system (C3 and membrane attack complex = MAC). Additionally, we carried out quantitative real-time PCRs (qRT-PCR; n=5/group).
The number of RGCs was unaltered after 5 and 10 weeks (p>0.05). However, a significant RGC loss in βb1-CTGF mice (25.5±2.8 cells/mm) was noted at 15 weeks compared to WT (43.6±3.0 cells/mm; p=0.0005). At 15 weeks, we also noted a downregulation of the RGC marker Pou4f1 via qRT-PCR (0.4-fold; p=0.02). The proportion of apoptotic RGCs was significantly higher in βb1-CTGF animals at all points in time (5 weeks: p=0.005; 10 weeks: p=0.02; 15 weeks: p=0.002). We also observed a significant increase of C3+ cells in βb1-CTGF retinae (8.5±0.8 cells/mm) compared to WT (5.9±0.7 cells/mm; p=0.03) at 5 weeks. After 10 weeks, a trend to more C3+ cells was observed (p=0.058), whereas at 15 weeks, no alterations could be seen anymore (p>0.05). The terminal complement component MAC was not altered at all investigated time points via immunohistology. However, a significant upregulation of C5 mRNA levels was noted at 15 weeks (2.3-fold; p=0.03).
In βb1-CTGF mice, the RGC degeneration occurred slowly over time. This slow progression is also known for human glaucoma patients. Interestingly, the complement system is more active at early points in time, suggesting a key role in cell death in this new glaucoma model.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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