Upregulation of Proteolytic Pathways and Altered Protein Biosynthesis Underlie Retinal Pathology in a Mouse Model of Alzheimer's Disease.

Increased amyloid β (Aβ) aggregation is a hallmark feature of Alzheimer's disease (AD) pathology. The APP/PS1 mouse model of AD exhibits accumulation of Aβ in the retina and demonstrates reduced retinal function and other degenerative changes. The overall molecular effects of AD pathology on the retina remain undetermined. Using a proteomics approach, this study assessed the molecular effects of Aβ accumulation and progression of AD pathology on the retina. Retinal tissues from younger (2.5 months) and older 8-month APP/PS1 mice were analysed for protein expression changes. A multiplexed proteomics approach using chemical isobaric tandem mass tags was applied followed by functional and protein-protein interaction analyses using Ingenuity pathway (IPA) and STRING computational tools. We identified approximately 2000 proteins each in the younger (upregulated 50; downregulated 36) and older set of APP/PS1 (upregulated 85; downregulated 79) mice retinas. Amyloid precursor protein (APP) was consistently upregulated two to threefold in both younger and older retinas (p < 0.0001). Mass spectrometry data further revealed that older APP/PS1 mice retinas had elevated levels of proteolytic enzymes cathepsin D, presenilin 2 and nicastrin that are associated with APP processing. Increased levels of proteasomal proteins Psma5, Psmd3 and Psmb2 were also observed in the older AD retinas. In contrast to the younger animals, significant downregulation of protein synthesis and elongation associated proteins such as Eef1a1, Rpl35a, Mrpl2 and Eef1e1 (p < 0.04) was identified in the older mice retinas. This study reports for the first time that not only old but also young APP/PS1 animals demonstrate increased amyloid protein levels in their retinas. Quantitative proteomics reveals new molecular insights which may represent a cellular response to clear amyloid build-up. Further, downregulation of ribosomal proteins involved in protein biosynthesis was observed which might be considered a toxicity effect.