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K.A. Howes, Y. Sauvé, N. Roychowdhury, A. Marks, J.M. Frederick, W. Baehr; Induction of Age-related Macular Degeneration (AMD) by Advanced Glycation End (AGE) Products and S100B . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1728.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To explore the involvement of RAGE-mediated cellular activation in the etiology of AMD. Methods: Immunocytochemistry using AGE- and RAGE-specific antibodies on tissue of AMD vs. control donor eyes; full field corneal electroretinograms of dark-adapted S100B transgenic mice; real-time RT PCR; light microscopy. Results: AMD, the leading cause of blindness in the elderly, is characterized by progressive damage to the retina’s supportive epithelia and photoreceptor cell loss. In aging disorders, AGE products incite progressive tissue damage through chronic AGE receptor (RAGE)-mediated cellular activation. In AMD donor eyes, immunocyto-chemistry reveals specific upregulation of two AGE receptors (RAGE and 80K-H) in RPE cells adjacent to sites of AGE deposition. ARPE-19 cell cultures treated with AGE-BSA show dose-response increases in RAGE expression. An additional RAGE ligand, S100B, similarly induces RAGE expression in ARPE-19 cells at micromolar concentrations. S100B is an EF-hand Ca2+ -binding protein present in the CNS at low concentrations, but can be upregulated to toxic levels in neurodegenerative diseases. Both RAGE ligands induce known receptor-mediated downstream events including nuclear translocation of the transcription factor NFΚB and enhanced expression of RAGE (assayed by real time RT-PCR). Cellular activation sustained by chronic availability of either AGE-BSA or S100B is cytotoxic to ARPE-19 cells. Further, transgenic mice overexpressing the retinal RAGE ligand, S100B, similarly reveal upregulated RAGE and 80K-H in the RPE and show a retinal pathology resembling AMD including premature lipofuscin accumulation at 2 months followed by significantly reduced ERG a- and b-waves at 6 months of age. Conclusion: We present evidence that RAGE-mediated cellular activation is a pathophysiological determinant leading to AMD in patients, and to an AMD-like phenotype in the S100B transgenic mouse model. As no current therapy halts vision loss in AMD, this RAGE-mediated pathway may have significance for pharmacologic intervention, and the S100B transgenic mouse will be a useful model to develop these strategies.
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