Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways
| Autor: | Roberta Borghi, Oliviero Danni, Mark A. Smith, Elena Tamagno, Alessandra Piccini, Michela Guglielmotto, Paola Bardini, Annalisa Davit, George Perry, Gianni Santoro, Maurizio Parola, Massimo Tabaton |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Cell signaling
Alzheimer’s disease beta-site APP cleaving enzyme cell signaling 4-hydroxynonenal oxidative stress stress-activated protein kinase Enzyme Activators Apoptosis Protein Serine-Threonine Kinases p38 Mitogen-Activated Protein Kinases Biochemistry Cell Line 4-Hydroxynonenal Phosphatidylinositol 3-Kinases Cellular and Molecular Neuroscience chemistry.chemical_compound Proto-Oncogene Proteins Endopeptidases Amyloid precursor protein Aspartic Acid Endopeptidases Humans Phosphatidylinositol Protein kinase B Neurons Aldehydes biology Kinase JNK Mitogen-Activated Protein Kinases Up-Regulation DNA-Binding Proteins STAT1 Transcription Factor Beta-secretase 1 chemistry Mitogen-activated protein kinase Trans-Activators biology.protein Amyloid Precursor Protein Secretases Proto-Oncogene Proteins c-akt Signal Transduction |
| Popis: | 4-Hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, up-regulates expression of the beta-site APP cleaving enzyme (BACE-1), an aspartyl protease responsible for the beta-secretase cleavage of amyloid precursor protein (AbetaPP), and results in increased levels of amyloid beta (Abeta) peptide. The mechanisms underlying this remain unclear but are of fundamental importance because prevention of BACE-1 up-regulation is viewed as an important therapeutic strategy. In this study, we exposed NT(2) neurons to a range of HNE concentrations (0.5-5 microm) that elicited an up-regulation of BACE-1 expression, a significant increase in intracellular and secreted levels of Abeta peptides as well as apoptosis involving poly-ADP ribose polymerase cleavage and activation of caspase 3. To delineate the molecular events involved in HNE-mediated BACE-1 activation, we investigated the involvement of stress-activated protein kinases (SAPK), signal transducers and activators of transcription (STAT) and serine-threonine kinase B/phosphatidylinositol phosphate 3 kinase (Akt/PtdIns3K). Using specific pharmacological inhibitors, our results show that activation of c-Jun N-terminal kinases and p38(MAPK.), but not STAT or Akt/PtdIns3K, pathways mediate the HNE-dependent up-regulation of BACE-1 expression. Therefore, HNE, an oxidative stress mediator detected in vivo in the brains of Alzheimer's disease patients, may play a pathogenetic role in Alzheimer's disease by selectively activating SAPK pathways and BACE-1 that regulate the proteolytic processing of AbetaPP. |
| Databáze: | OpenAIRE |
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