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Kanishka Pushpitha, Mehdi Mirzaei, Nitin Chitranshi, Liting Deng, Vivek Kumar Gupta, Stuart L Graham; Crystallin downregulation as a converging link between AD and glaucoma induced retinal pathology. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4862.
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© ARVO (1962-2015); The Authors (2016-present)
Crystallins are heterogenous proteins that are well expressed in the retina and have been implicated in retinal ganglion cell (RGC) survival and axonal regeneration. Intravitreal injections of crystallins are shown to improve RGC survival in glaucoma. Further, crystallin upregulation has also been associated with pathological hallmarks of Alzheimer’s (AD) brains. The effects of AD pathology on the crystallin expression changes in retina has the potential to unravel common molecular pathways underlying these two disorders, but remains unexplored so far. We examined crystallin expression changes in the retinas of an APP/PS1 mouse model of AD and contrasted the findings with retinal changes in an animal model of experimental glaucoma.
WT and APP/PS1 (8 month) mice retinas were examined using mass spectrometry (MS) and data obtained was subjected to in-depth computational analysis using STRING and PANTHER tools. The retinal biochemical changes were evaluated using WB and IF analysis of the retinal sections (n=10). The findings were contrasted with retinal changes in rat model of increased IOP caused by microbead induced glaucoma (n=10).
MS data revealed significantly reduced expression levels of crystallin proteins in the retinas of both AD (p<0.05) and glaucoma (p<0.05) models compare to respective control animals. Immunoblotting analysis of retinal lysates of AD mice demonstrated significantly decreased αB and βB2-Crystallins (p<0.02) along with βB3-Crystallin downregulation (p<0.01) compared to the WT counterparts. IF staining further revealed lower expression levels of the αβ-, βB2- and βB3 crystallins in the retinas in AD pathology (n=3). IF analysis of the experimental glaucoma retinas further corroborated these findings with reduced expression levels of αB-, βB2- and βB3-Crystallin proteins (n=3).
This study provides evidence for various crystallin isoforms that are specifically affected in the retinas of an animal AD model and in retinal injury caused by experimental glaucoma. Our findings implicate converging neurodegenerative mechanisms in these two disorders that might lead to downregulation of the crystallin network. Further studies will examine the potential neuroprotective effects of modulating crystallins in the retina, which in turn could help design new treatment strategies to preserve or regenerate neurons.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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