title: Double-Edged Roles of Nitric Oxide Signaling on APP Processing and Amyloid-β Production In Vitro: Preliminary Evidence from Sodium Nitroprusside.
abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is thought to be caused in part by the age-related accumulation of amyloid-β (Aβ) in the brain. Recent findings have revealed that nitric oxide (NO) modulates the processing of amyloid-β precursor protein (APP) and alters Aβ production; however, the previously presented data are contradictory and the underlying molecular mechanisms are still incomplete. Here, using human SH-SY5Y neuroblastoma cells stably transfected with wild-type APPwt695, we found that NO, derived from NO donor sodium nitroprusside (SNP), bi-directionally modulates APP processing in vitro. The data from ELISA and Western blot (WB) tests indicated that SNP at lower concentrations (0.01 and 0.1 μM) inhibits BACE1 expression, thus consequently suppresses APP β-cleavage and decreases Aβ production. In contrast, SNP at higher concentrations (10 and 20 μM) biases the APP processing toward the amyloidogenic pathway as evidenced by an increased BACE1 but a decreased ADAM10 expression, together with an elevated Aβ secretion. This bi-directional modulating activity of SNP on APP processing was completely blocked by specific NO scavenger c-PTIO, indicating NO-dependent mechanisms. Moreover, the anti-amyloidogenic activity of SNP is sGC/cGMP/PKG-dependent as evidenced by its reversal by sGC/PKG inhibitions, whereas the amyloidogenic activity of SNP is peroxynitrite-related and can be reversed by peroxynitrite scavenger uric acid. In summary, these present findings predict a double-edged role of NO in APP processing in vitro. Low (physiological) levels of NO inhibit the amyloidogenic processing of APP, whereas extra-high (pathological) concentrations of NO favor the amyloidogenic pathway of APP processing. This preliminary study may provide further evidence to clarify the molecular roles of NO and NO-related signaling in AD and supply potential molecular targets for AD treatment.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
authors.forename: Zheng-Xu
authors.initials: ZX
authors.lastname: Cai
authors.affiliation: Laboratory Center, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
authors.forename: Hui-Shu
authors.initials: HS
authors.lastname: Guo
authors.affiliation: Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China.|Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Sciences, Liaoning Normal University, Dalian, 116029, China.
authors.forename: Che
authors.initials: C
authors.lastname: Wang
authors.affiliation: Center for Translational Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.affiliation: Center for Translational Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Center for Translational Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China.
authors.forename: Zhao-Fei
authors.initials: ZF
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China.
authors.forename: Yin-Wang
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Center for Translational Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China. wdle@sibs.ac.cn.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Le
authors.affiliation: Center for Translational Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China. lisong_spu2005@yahoo.com.
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D006152:Cyclic GMP / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002227:Carbazoles; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D013481:Superoxides; C073601:KT 5823; D030421:Peroxynitrous Acid; D009599:Nitroprusside; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D006152:Cyclic GMP
keywords: Amyloid-β; Amyloid-β precursor protein; Nitric oxide; Peroxynitrite; Sodium nitroprusside; sGC/cGMP/PKG signaling pathway