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Thomas Ach, Pia Stockinger, Christine Schmitt, Christine A. Curcio, Michael Sendtner, Jost Hillenkamp; Ciliary neurotrophic factor (CNTF) in the retina: age and disease related expression in humans and mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3104.
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© ARVO (1962-2015); The Authors (2016-present)
Ciliary neurotrophic factor (CNTF) has shown neuroprotective effects on ganglion cells and photoreceptors in several animal models. However, in vivo use in humans failed to show significant protection in age-related macular degeneration (AMD) and other retinal diseases. This discrepancy may be due to species-related retinal differences of CNTF secretion and/or cellular effects. The aim of our study is to compare age- versus disease-related changes in CNTF and CNTF dependent phosphorylated signal transducer and activator of transcription 3 (pSTAT3) levels both in murine and human retinas.
Retina samples derived from: 1. CNTF-/- and corresponding control C57Bl6 (wildtype, WT) mice at different ages (6, 18, 54 wks); 2. human donors (>80 yrs; normal macula or AMD). Retina sections (10 µm) were prepared for immunofluorescence (IF), stained with primary (CNTF, pSTAT3, cell specific markers (e.g., vimentin)) and secondary antibodies (Alexa 568, Alexa 647), and imaged using a confocal microscope (Olympus, 60x oil immersion). Retinal morphology was viewed with bright-field microscopy. All images were further processed with the microscope's software and FIJI. Appropriate local ethics committee approved all studies.
In WT mice, CNTF expression was evident in ganglion cells, Müller cells, and photoreceptor inner segments, with an age-dependent increase. No signal was detectable in CNTF-/-mice. Gross retinal morphology was similar in CNTF-/- and WT mice. In CNTF-/-mice, pSTAT3 is markedly upregulated in ganglion cells and inner nuclear layer vs WT. First results of normal human macula showed expression patterns comparable to WT mice for both CNTF and pSTAT3.
CNTF seems to be expressed in all retinal layers, hence CNTF may affect all retinal cell types. Interestingly, CNTF deficiency did not show obvious morphological retinal changes, and intracellular activation of STAT3 was increased instead of decreased in CNTF-/- retinae, indicating that compensatory signaling mechanisms are activated. Ongoing studies using human tissues will further elaborate expression patterns in diseased retina (i.e. AMD). These findings will help elucidate differences in species-specific protein expression and effects with the aim to develop future therapy strategies.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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