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

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Abstract

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.

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Acknowledgements

We acknowledge the support from the Ophthalmic Research Institute of Australia, National Health and Medical Research Council (NHMRC) and Hillcrest Foundation. The mass spectrometry analysis in this study was conducted at the Australian Proteome Analysis Facility supported by the Australian Government’s National Collaborative Research Infrastructure Scheme (NCRIS).

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  1. Mehdi Mirzaei and Kanishka Pushpitha contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Sciences, Macquarie University, Sydney, NSW, Australia

    Mehdi Mirzaei, Liting Deng, Matthew J. McKay, Karthik Kamath, Dana Pascovici, Jemma X. Wu, Ghasem Hosseini Salekdeh & Paul A. Haynes

  2. Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia

    Mehdi Mirzaei, Kanishka Pushpitha, Nitin Chitranshi, Rashi Rajput, Abu Bakr Mangani, Yogita Dheer, Angela Godinez, Stuart L. Graham & Vivek K. Gupta

  3. Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, Australia

    Mehdi Mirzaei, Matthew J. McKay, Karthik Kamath, Dana Pascovici & Jemma X. Wu

  4. School of Medicine, Deakin University, Melbourne, VIC, Australia

    Veer Gupta

  5. Department of Molecular Systems Biology, Cell Science Research Center, Royan, Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Ghasem Hosseini Salekdeh

  6. School of Medicine, Western Sydney University, Campbelltown, NSW, Australia

    Tim Karl

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Electronic Supplementary Material

Supplementary Figure 1:

Protein interaction and functional analysis. A, B. both young and older APP/PS1 mice respectively used to understand biochemical and physiological retinal anomalies cause due to AD progression with age. (PNG 395 kb)

High resolution image (TIF 19972 kb)

Supplementary Figure 2:

Immunostaining of the old retinal sections from WT and APP/PS1 mice illustrating nicastrin (Red–Cy3) expression (blue-DAPI) (n=3). Overexpressed locations were indicated by the white arrowheads. Scale=50 μm. (PNG 261 kb)

High resolution image (TIF 18151 kb)

Supplementary Figure 3:

Relative fluorescence intensity of the GCL region of immunostained sections as labelled above each graph. The sections were compared between WT and APP retinal staining. Aβ (Fig. 5C); Presenilin 1, Tau, pTau Ser404 (Fig. 6 B,C,D), Cathepsin B (Fig. 7B), PSMB2 (Fig. 7D), MRPL2 (Fig. 8B), EEF1E1 (Fig. 8D), αB Crystallin (Fig. 9B), βB2 Crystallin (Fig. 9D) and βB3 Crystallin (Fig. 9F), (n=3 each) (****p<0.0001, ***p<0.001, *p<0.01). (PNG 303 kb)

High resolution image (TIF 2821 kb)

Supplementary Table 1:

The list of proteins identified in the young retinal samples, including differentially expressed proteins identified from pairwise comparison test of APP/Ps1 vs. WT. The table 1 contains 4 independent sheets; Sheet 1- list of quantified proteins in the TMT experiments number 1 (younger retina), Sheet 2- list of differentially expressed proteins (APP vs WT comparison student t-test, p-value ≤ 0.05 and ≥ 1.15-fold difference), Sheet 3 and Sheet 4- list of down-regulated protein and list of up-regulated proteins respectively. Column A represents: UniProt ID; Column B: Peptide counts; Column C-G: fold changes ratios obtained from the TMT reporter ion intensities of APP replicates (129N, 129C, 130 N, 130 C and 131) versus the reference replicate 126 (one of the WT replicates); Column H-K: fold change ratios obtained from the TMT reporter ion intensities of WT replicates (127N, 127C, 128N, 128C) versus the reference replicate 126 (one of the WT replicates); Column L: p-values generated from APP vs WT t-test comparison test (p-value ≤ 0.05 highlighted as yellow); Column M: Max fold change of mean ration of APP vs WT; Column N: mean value of the fold change ratio of APP replicates vs reference replicate (126), purple: up-regulated, green: down-regulated; Column O: mean value of the fold change ratio of WT replicates vs reference replicate (126), purple: up-regulated, green: down-regulated ; Column P: Protein name/description and Column Q: Gene ontology information of every protein. (XLSX 840 kb)

Supplementary Table 2:

The list of proteins identified in the old retina samples, including differentially expressed proteins from pairwise comparison test of APP/Ps1 vs. WT. The table 2 contains 4 independent sheets; Sheet 1-list of quantified proteins in the TMT experiments number 1 (older retina), Sheet 2- list of differentially expressed proteins (APP vs WT comparison student t-test, p-value ≤ 0.05 and ≥ 1.15-fold difference), Sheet 3 and 4- list of down-regulated protein and list of up-regulated proteins respectively. Column A represents : UniProt ID; Column B: Peptide counts; Column C-G: fold changes ratios obtained from the TMT reporter ion intensities of APP replicates (129N, 129C, 130 N, 130 C and 131) versus the reference replicate 126 (one of the WT replicates); Column H-K: fold change ratios obtained from the TMT reporter ion intensities of WT replicates (127N, 127C, 128N, 128C) versus the reference replicate 126 (one of the WT replicates); Column L: P-values generated from APP vs WT t-test comparison test (p-value ≤ 0.05 highlighted as yellow); Column M: Max fold change of mean ration of APP vs WT; Column N: mean value of the fold change ratio of APP replicates vs reference replicate (126) - purple: up-regulated, green: down-regulated; Column O: mean value of the fold change ratio of WT replicates vs reference replicate (126), purple: up-regulated, green: down-regulated; Column P: Protein name/description; Column Q: Gene ontology information of every protein (XLSX 884 kb)

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Mirzaei, M., Pushpitha, K., Deng, L. et al. Upregulation of Proteolytic Pathways and Altered Protein Biosynthesis Underlie Retinal Pathology in a Mouse Model of Alzheimer’s Disease. Mol Neurobiol 56, 6017–6034 (2019). https://doi.org/10.1007/s12035-019-1479-4

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