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Vivek Kumar Gupta, Mehdi Mirzaei, Yunqi Wu, Liting Deng, Nitin Chitranshi, Stuart L Graham; Selective upregulation of proteolytic enzymes and altered protein biosynthesis in the retina of Alzheimer’s disease mouse model. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3528.
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© ARVO (1962-2015); The Authors (2016-present)
Increased amyloid β (Aβ) aggregation is a hallmark feature of Alzheimer’s disease pathology. We have reported that the APP/PS1 mouse model of AD exhibits accumulation of Aβ in their retinas and demonstrate reduced retinal function and other degenerative changes. The molecular effects of AD pathology particularly on the retina remain undetermined. This study analysed both young and ageing APP/PS1 mice using proteomics approaches to assess the molecular effects of Aβ accumulation and progression of AD pathology on the retina.
Retinal tissues from young (2.5 months) and ageing (13-16 months) APP/PS1 mice (n=10) were analysed for protein expression changes. A multiplexed proteomics using chemical isobaric tandem mass tags using LC/MS was carried out. Detailed functional and protein-protein interaction analyses were performed using Ingenuity pathway analysis, STRING and Panther computational tools.
Mass spectrometry identified around 2000 proteins each in the young and ageing APP/PS1 mice retinas. Differential levels of proteins were identified in both young (Upregulated 50; downregulated 36) and ageing (Upregulated 85; downregulated 78) retinas compared to the WT eyes (p<0.05). Amyloid precursor protein (APP) was consistently upregulated 2-3 fold in both young and ageing retinas (p<0.0001). Amongst these, computational analysis revealed that aged APP/PS1 mice demonstrated elevated levels of proteolytic enzymes cathepsin D, presenilin 2 and nicastrin that are associated with APP processing (>1.2 fold; p<0.05). Increased levels of proteasomal proteins Psma5, Psmd3 and Psmb2 (>1.15 fold; p<0.05) were also observed in the aged AD retinas. Further, in contrast to the young animals, ageing mice demonstrated significant downregulation of protein synthesis and elongation associated proteins such as Eef1a1, Rpl35a, Mrpl2, Eef1e1(p<0.04).
This study confirms that not only ageing APP/PS1 mice demonstrate increased levels of amyloid protein in their retinas, but younger mice as well. Quantification proteomics highlight upregulation of proteolytic enzymes and proteasome components, specifically in the ageing APP/PS1 mice retinas which may represent a cellular response to clear deposits. In addition downregulation of ribosomal proteins involved in protein biosynthesis was observed which may be a toxicity effect.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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