PKC delta and NADPH oxidase in AGE-induced neuronal death.
Advanced glycation end product (AGE) accumulation in brain is believed to contribute to neuronal death in several neurodegenerative diseases. Neurons exposed to AGEs undergo oxidative stress, but the molecular mechanisms able to induce ROS generation and cell death are not yet clear. In this work, we exposed SH-SY5Y neuroblastoma cells to glycated albumin, as a model of AGE-modified protein, and we observed that cells differentiated by retinoic acid died after AGE exposure, through anion superoxide and peroxide generation, while undifferentiated cells resulted resistant. Retinoic acid induced marked increase in p47phox expression and in catalytic activity of PKC delta: the upregulation of a pathway involving NADPH oxidase and PKC delta is likely to be responsible for neuronal susceptibility to AGE. This hypothesis is confirmed by the fact that pre-treatments of differentiated cells with DPI, an inhibitor of NADPH oxidase, or with rottlerin, an inhibitor of PKC delta, were able to prevent AGE-induced neuronal death.
Nitti
Mariapaola
M
Department of Experimental Medicine, General Pathology Section, University of Genoa, Via L.B. Alberti 2, 16132 Genoa, Italy. paonit@medicina.unige.it
Furfaro
Anna L
AL
Traverso
Nicola
N
Odetti
Patrizio
P
Storace
Daniela
D
Cottalasso
Damiano
D
Pronzato
Maria A
MA
Marinari
Umberto M
UM
Domenicotti
Cinzia
C
D000704:Analysis of Variance; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology
C000593871:AGER protein, human; D017127:Glycation End Products, Advanced; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D014212:Tretinoin; D019255:NADPH Oxidases; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases