title: The Possible Mechanism of Advanced Glycation End Products (AGEs) for Alzheimer's Disease.
abstract: Amyloid precursor protein (APP) has been modified by β and γ-secretase that cause amyloid deposits (plaques) in neuronal cells. Glyceraldhyde-derived AGEs has been identified as a major source of neurotoxicity in Alzheimer's disease (AD). In a previous study, we demonstrated that glyceraldehyde-derived AGEs increase APP and Aβ via ROS. Furthermore, the combination of AGEs and Aβ has been shown to enhance neurotoxicity. In mice, APP expression is increased by tail vein injection of AGEs. This evidence suggests a correlation between AGEs and the development of AD. However, the role played by AGEs in the pathogenesis of AD remains unclear. In this report, we demonstrate that AGEs up-regulate APP processing protein (BACE and PS1) and Sirt1 expression via ROS, but do not affect the expression of downstream antioxidant genes HO-1 and NQO-1. Moreover, we found that AGEs increase GRP78 expression and enhance the cell death-related pathway p53, bcl-2/bax ratio, caspase 3. These results indicate that AGEs impair the neuroprotective effects of Sirt1 and lead to neuronal cell death via ER stress. Our findings suggest that AGEs increase ROS production, which stimulates downstream pathways related to APP processing, Aβ production, Sirt1, and GRP78, resulting in the up-regulation of cell death related pathway. This in-turn enhances neuronal cell death, which leads to the development of AD.
authors.affiliation: Graduate Institute of Medical Sciences, Collage of Health Science, Chang Jung Christian University, Tainan, Taiwan.|Innovate Research Center of Medicine, Chang Jung Christian University, Tainan, Taiwan.
authors.forename: Shun-Yao
authors.initials: SY
authors.lastname: Ko
authors.affiliation: Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Hshin-An
authors.initials: HA
authors.lastname: Ko
authors.affiliation: Department of Bioscience Technology, Collage of Health Science, Chang Jung Christian University, Tainan, Taiwan.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Chu
authors.affiliation: Department of Dental Hygiene, China Medical University, Taichung, Taiwan.
authors.forename: Tzong-Ming
authors.initials: TM
authors.lastname: Shieh
authors.affiliation: Graduate Institute of Medical Sciences, Collage of Health Science, Chang Jung Christian University, Tainan, Taiwan.|Innovate Research Center of Medicine, Chang Jung Christian University, Tainan, Taiwan.
authors.forename: Tzong-Cherng
authors.initials: TC
authors.lastname: Chi
authors.affiliation: Graduate Institute of Medical Sciences, Collage of Health Science, Chang Jung Christian University, Tainan, Taiwan.|Innovate Research Center of Medicine, Chang Jung Christian University, Tainan, Taiwan.
authors.forename: Hong-I
authors.initials: HI
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medical Sciences, Collage of Health Science, Chang Jung Christian University, Tainan, Taiwan.
authors.forename: Weng-Cheng
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Innovate Research Center of Medicine, Chang Jung Christian University, Tainan, Taiwan.
authors.forename: Shu-Shing
authors.initials: SS
authors.lastname: Chang
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000975:Antioxidants / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents; D058225:Plaque, Amyloid / Q000473:pathology*; D053764:Presenilin-1 / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; C000595707:BCL2 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D017127:Glycation End Products, Advanced; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013267:Stilbenes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D053829:Amyloid Precursor Protein Secretases; C505407:CASP3 protein, human; D053148:Caspase 3; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol