title: Amyloid-beta mediates the receptor of advanced glycation end product-induced pro-inflammatory response via toll-like receptor 4 signaling pathway in retinal ganglion cell line RGC-5.
abstract: Patients with diabetes mellitus have an increased risk of developing Alzheimer's disease. Amyloid-β, a product of amyloid precursor protein, is associated with neuro-inflammation in patients with Alzheimer's diseases. The correlation between amyloid-beta and advanced glycation end products, which accumulate in tissue of diabetic patients, is not clear. The aims of this study were to determine the effect of advanced glycation end product on the expression of amyloid precursor protein/amyloid-beta and associated pro-inflammatory responses in retinal ganglion cell line RGC-5. Treatment with advanced glycation end product produced upregulation of amyloid precursor protein and increased secretion of amyloid-β(1-40). Additionally, amyloid-β(1-40) induced toll-like receptor 4-dependent phosphorylation of tyrosine in myeloid differentiation primary response gene (88). We found that N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, a γ-secretase inhibitor, reduced the secretion of amyloid-β(1-40) and inhibited the advanced glycation end product-induced activation of myeloid differentiation primary response gene (88). Amyloid-β(1-40) induced the activation of NF-κB and the expression of TNFα mRNA. Knockdown of toll-like receptor 4 inhibited the amyloid-β(1-40)-induced phosphorylation of p65 in NF-κB. Additionally, the nuclear translocation of p65 and transcriptions of TNFα were inhibited by siRNA knockdown of receptor of advanced glycation end product or toll-like receptor 4. The advanced glycation end product-induced secretion of VEGF-A was also reduced by knockdown of toll-like receptor 4. Taken together, our data suggested that amyloid-β(1-40) mediates the interaction between receptor of advanced glycation end product and toll-like receptor 4. Inhibition of the toll-like receptor 4 is an effective method for suppressing the amyloid-β(1-40)-induced pro-inflammatory responses in RGC-5 cells.
authors.affiliation: Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; The Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taiwan.
authors.forename: Jong-Jer
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine and Nuclear Medicine, Division of Endocrinology and Metabolism, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: I-Hui
authors.initials: IH
authors.lastname: Yang
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; The Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taiwan. Electronic address: jhchuang@adm.cgmh.org.tw.
authors.forename: Jiin-Haur
authors.initials: JH
authors.lastname: Chuang
mesh_terms: D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D017127:Glycation End Products, Advanced / Q000502:physiology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000502:physiology*; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C000593874:Ager protein, rat; D016229:Amyloid beta-Peptides; D017127:Glycation End Products, Advanced; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C467498:vascular endothelial growth factor A, rat
keywords: Amyloid-beta; Myeloid differentiation primary response gene (88) (MyD88); Receptor of advanced glycation end product (RAGE); Retina; Toll-like receptor 4 (TLR4)