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EP Rakoczy, D Zhang, M Lai, N Barnett, I Constable; Development of an animal model for Age Related Macular Degeneration . Invest. Ophthalmol. Vis. Sci. 2002;43(13):865.
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Purpose: This project aimed to investigate whether impairement of a randomly selected essential lysosomal enzyme could induce photoreceptor outer segment (POS) derived debris accumulation in the retinal pigment epithelium (RPE) in a time dependent fashion. In addition, this work set out to demonstarte if this gradual, abnormal debris accumulation can subsequently induce the development of drusen, basal laminar deposit, photoreceptor loss, RPE cells proliferation/loss similar to those observed in sufferers of AMD, particulraly geographic atrophy (GA). Methods: Transgnic mice carrying a deletion at the enzymatic activation cleavage site of cathepsin D, between 241-246 base positions (mcd) was produced and the homozygous mcd/mcd animals were analysed at 12 months of age using, fundus photgraphy, ERG, histology, immunohistochemistry, tunnel assay, electron microscopy. Results: The expression of the mutated CatD was demonstrated in mcd/mcd animals. mcd/mcd animals demonstrated the accumulation of abnormal amount of undigested POS debris that reamined immunoreactive. Fundus photography showed pigmentary changes in 100% of mcd/mcd mice at the age of 11-12 months. The severity of pimentary changes increased in a time dependent manner affecting 100% of the retina by 18 months of age. Age matched control animals did not show pigmentary changes. There was a decerase in a and b waveresponses. Histological analysis has shown significant morphological changes in the RPE layer sometimes accompanied with RPE proliferation. In these regions there was significant increase in the size of RPE cells. EM has confirmed significant pigmentray changes in the RPE cells, the formation of vacoules and basal laminar and linear deposits.Tunnel assay demonstarted an increase in apoptotic photoreceptor cells death in mcd/mcd mice. Conclusion: These results demonstrated that the the development of retinal changes resembling AMD, or more specifically GA, is not necessarily linked to a single gene mutation but most probably due to the abnormal accumulation of a non-specific POS debris in the RPE cells.
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