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Hayley S. Waugh, Kathryn Cimdins, Ian A. Trounce, Jonathan G. Crowston; Amyloid Precursor Protein-mediated Neuroprotection In The Aged Retina. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3078.
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Increasing age is a major risk factor for neuronal loss in Alzheimer’s disease and retinal ganglion cell (RGC) loss in glaucoma. Oxidative stress associated with aging increases beta cleavage (amyloidogenic processing) of amyloid precursor protein (APP) resulting in elevated levels of toxic amyloid beta peptide, which has recently been found to be increased in the inner retina of rodent glaucoma models. Beta cleavage also results in a decrease in the neurotrophic alpha-cleavage APP product, sAPPα, and we hypothesize that loss of this trophic factor may render aged RGCs more susceptible to injury.
Cell culture experiments were used to test whether sAPP could protect human neuronal cells against a mitochondrial toxin rotenone, which has been shown to preferentially kill RGCs in rodents. Donor human eyes were analysed for APP products using western blotting of retina and vitreous fluid. Rodent eyes were examined for APP expression using immunohistochemistry.
sAPPα was neuroprotective against rotenone insult in SHSY cells, (p<0.005) and this protection was linked to activation of the Akt kinase (p<0.05). APP expression in rodent retina was limited to the RGC layer and Muller cells. In human retina, the expression of APP was increased with age (N=12, p<0.04). Surprisingly, we found high levels of sAPPα expression in the vitreous of human eyes, suggesting a protective function exerted at the inner retina.
We have established that sAPPα is a potent neuroprotectant against an agent that has been used to model RGC loss in rodent. In human retina APP is highly expressed by RGCs which appear to use the vitreous to ‘bath’ the inner retina with this protein.
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