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Ling-Ping Cen; AAV-mediated Expression Of GAP-43 Aggravates Retinal Ganglion Cell Death In Experimental Chronic Glaucomatous Injury. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2451.
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To examine whether adeno-associated viral (AAV) vector mediated overexpression of growth-associated protein-43 (GAP-43) has protective or deleterious effects on retinal ganglion cell (RGC) survival in laser-induced chronic intraocular pressure (IOP) elevation injury.
Adult Fischer 344 rats received unilateral intravitreal injection of either normal saline, AAV-green fluorescent protein (GFP) or a bicistronic AAV vector encoding GAP-43 and GFP (AAV-GAP-43-GFP). Two weeks later, experimental chronic glaucoma was induced in the injected eyes by scaring the trabecular meshwork with diode laser. IOP was measured with an impact (rebound) tonometer. Survival of RGCs was estimated by quantification of βIII-tubulin+ neurons directly on retinal wholemounts after three weeks of IOP elevation. Transfection efficiency of target genes was assessed by direct view of GFP and Western blot analysis of GAP-43.
Quantification of βIII-tubulin immunostaining revealed that, compared to uninjured eyes (1172±80 cells/mm2), three weeks of laser-induced IOP elevation led to a 60% decline in RGC survival (496±136 cells/mm2). Transfection with control vector AAV-GFP by itself did not have a significant effect on RGC viability (468±124 cells/mm2). Overexpression of GAP-43 in RGC cell bodies and axons via AAV-GAP-43-GFP led to more severe RGC death (260±112 cells/mm2) in IOP elevated eyes, resulting in 80% loss of the total RGC population in a retina.
Overexpression of GAP-43 aggravates RGC death in experimental chronic IOP elevation injury. GAP-43 is upregulated in RGCs regenerating after optic nerve injury, thus the finding that this same protein is deleterious to RGC viability after chronic IOP elevation may aid in our understanding of the mechanisms involved in RGC loss in glaucoma, and how best to treat this condition.
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