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J. Cui, K. Kurji, T. K. Lin, S. Prasad, L. Kojic, J. A. Matsubara; Microarray-Based Gene Set Analysis: Pathway Analysis of Advanced Glycation Endproduct (AGEs) or Amyloid Beta (Aβ) Stimulation of Human RPE in vitro. Invest. Ophthalmol. Vis. Sci. 2009;50(13):707.
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© ARVO (1962-2015); The Authors (2016-present)
Two components of drusen, hallmark deposits in AMD, are AGEs and Aβ. AGEs, products of covalent modification of proteins, accumulate with age and are linked to several age-related disorders. Aβ is a peptide known for its role in Alzheimer’s disease. Our earlier study on RPE in vitro identified that both proteins are pro-inflammatory. This study compares pathway analysis of gene expression changes associated with AGEs and Aβ stimulation of human RPE in vitro.
Genome-wide changes in gene expression of RPE stimulated with Aβ 1-40 oligomeric form (0.3 µM) or AGEs (10 µg/ml) for 24h were studied with Agilent Oligo Microarrays. Gene expression data for AGEs and Aβ stimulation were evaluated by Ingenuity Pathway Analysis. The analysis used published knowledge databases to identify dynamically generated biological networks, global canonical pathways and functions highly associated with gene expression after AGEs or Aβ stimulation. The significance value of a given canonical pathway, a measurement of the likelihood that the pathway is associated with the data set by random chance, was calculated using a right-tailed Fisher Exact Test, and values of p< 0.05 were assumed to be statistically significant.
Canonical pathways having significant numbers of up-regulated genes in AGEs treated RPE cells included: interferon signaling, role of pattern recognition receptors for bacteria/virus, activation of interferon regulatory factor (IRF) by cytosolic pattern recognition receptors, complement system, role of protein kinase in interferon induction, and PDGF signaling. The majority of the differentially expressed genes were immune related; chemokine (C-X-C motif) ligand 11 (CXCL11), a potent ligand for chemokine (C-X-C motif) receptor 3 (CXCR3), was upregulated 12.7 fold. Canonical pathways having significant numbers of up-regulated genes in Aβ treated RPE cells included: leukocyte extravasation signaling, natural killer cell signaling, hepatic cholestasis, farnesoid X receptor/retinoic X receptor activation, interleukin-10 (IL-10) signaling and complement system. The bulk of the differentially expressed genes were immune related, but apoptotic, angiogenic, and extracellular matrix genes were also affected.
Both Aβ and AGEs promote expression of inflammatory cytokines in RPE cells in vitro. The results suggest an increase in immunological and inflammatory activities in the RPE after Aβ or AGEs stimulation. Our data revealed evidence that AMD, amyloid diseases, and AGEs related disease may share common pathogenic pathways.
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