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C Bode, U Wolfrum; Apoptotic Photoreceptors of the Tubby Mouse Retina Die via an Apoptotic Caspase-3 Pathway and Are Phagocyted by Microglia Cells . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2729.
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Purpose:Purpose: Human Usher syndrome is the most common hereditary form of combined deafness and blindness. In the absence of a specific animal Usher model which exhibits retinal degeneration parallel to inner ear degeneration, we used the tubby mouse to analyse pathophysiologic processes leading to retina degeneration. Furthermore, we evaluated in this system the role of microglia cells during degeneration and the efficiency of anti-apoptotic strategies. Methods:Retinas of tubby and wild type mice were analyzed by light and immmunoelectron microscopy. Apoptotic cells were determined by the TUNEL-method. Activation of microglial cells were detected by specific markers. Caspase and macrophage inhibitors were intravitreally injected. Results:The retina of tubby mice developed normally. In mature tubby mouse retinas, dramatic disorganization occur and in photoreceptors, opsin was baso-laterally misrouted. TUNEL-labeling revealed that tubby photoreceptor cells die via apoptosis. The obtained apoptotic time course showed that the number of apoptotic photoreceptor cells peaked at p.n. day 19 before decreasing to a basal low number. Intravitreal injections of caspase inhibitors revealed that these apoptotic processes were mediated by caspase-3. Microglia staining and intravitreal injections of microglia inhibitors showed that in the tubby retina, activated microglia migrate to the outer retina where they phagocytized apoptotic cells. Conclusion: In the mature tubby mouse retina, apoptotic death of photoreceptors is the first indication for retinal degeneration. Apoptotic photoreceptors activated resident microglial cells which migrate to the sites of cell death phagocyte the cell debris. Apoptosis in the degenerating retina of tubby mice is mediated by caspase-3 activation. Specific caspase-3 inhibitions provide effective protection to photoreceptors in the tubby mouse retina and may be a potential tool for therapeutic strategies in human Usher syndrome.FAUN-Stiftung, Forschung contra Blindheit - Initiative Usher Syndrom e.V., Pinguin Stiftung.
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